Bicyclic amide derivatives and their use as muscle relaxants

ABSTRACT

Novel compounds of formula (I) ##STR1## wherein R 1 , R 2 , R 3  and R 4  are each selected from hydrogen and fluoro and at least one and not more than two is fluoro; 
     R 5  is selected from hydrogen and C 1  -C 4  alkyl; 
     R 6  is selected from hydrogen, C 1  -C 4  ally and hydroxy; or 
     R 5  and R 6  together with the ring carbon form a carbonyl group; 
     R 7  is selected from hydrogen and hydroxy, 
     R 8  and R 9  are each selected from hydrogen, C 1  -C 4  alkyl and cyclo(C 3  or C 4 ) alkyl or together with the nitrogen form a morpholino group; and 
     X is selected from a bond, methylene and --O-- and is always a bond or --O-- when any of R 5 , R 6  and R 7  is other than hydrogen and is always a bond when R 5  and R 6  together with the ring carbon form a carbonyl group; 
     and their salts and solvates have a number of uses as central muscle relaxants. In particular, treatment of conditions associated with abnormally raised skeletal muscle tone. They are of special value in the relaxation of skeletal muscle in spastic, hypertonic and hyperkinetic conditions.

This application is a 371 of PCT/GB94/01003 filed May 10, 1994.

The present invention relates to amide compounds, synthesis thereof,intermediates, salts and solvates thereof, pharmaceutical compositionscontaining them and the use of such compounds and compositions inmedicine and therapy, particularly as central muscle relaxants.

The major limiting side effects of many clinically effective centralmuscle relaxants and anticonvulsants are the induction of sedation andincoordination in the recipient, which severely limit their usefulness.Similar side effects are found with drugs used in the treatment ofanxiety, such as benzodiazepines. Although these effects may betransient, patients on such therapy are often unable to drive orparticipate in certain occupations.

It has now surprisingly been found that amides of formula (I) are potentcentral muscle relaxants and have a significantly reduced liability tosedation and incoordination compared with known agents.

In one aspect the present invention provides the novel compounds offormula (I) ##STR2## wherein R¹, R², R³ and R⁴ are each selected fromhydrogen and fluoro and at least one and not more than two is fluoro;

R⁵ is selected from hydrogen and C₁ -C₄ alkyl;

R⁶ is selected from hydrogen, C₁ -C₄ alkyl and hydroxy; or

R⁵ and R⁶ together with the ring carbon form a carbonyl group;

R⁷ is selected from hydrogen and hydroxy;

R⁸ and R⁹ are each selected from hydrogen, C₁ -C₄ alkyl and cyclo(C₃ orC₄)alkyl or together with the nitrogen form a morpholino group; and

X is selected from a bond, methylene and --O-- and is always a bond or--O-- when any of R⁵, R⁶ and R⁷ is other than hydrogen and is always abond when R⁵ and R⁶ together with the ring carbon form a carbonyl group;

and salts and solvates thereof.

As used herein,

"C₁ -C₄ alkyl" means a linear or branched chain alkyl group having 1, 2,3 or 4 carbon atoms;

"cyclo(C₃ or C₄)alkyl" means a cycloalkyl group having 3 or 4 carbonatoms;

"salts" means base salts formed when, in formula (I), one of R⁸ and R⁹is hydrogen; and

"solvates" means a combination, in definite proportions, of a compoundof formula (I) and a solvent therefor.

It will be appreciated that the compounds of formula (I) can exist invarious geoisomeric forms and as mixtures thereof in any proportions.The present invention includes within its scope such geoisomeric formsor mixtures of geoisomers, including the individual E and Z isomers ofthe compounds of formula (I) as well as mixtures of such isomers, in anyproportions.

Included within formula (I) are compounds wherein one or more carboncenters is/are chiral. The present invention includes within its scopeeach possible optical isomer substantially free from, i.e., associatedwith less than 5% of, any other optical isomer(s), as well as mixturesof one or more optical isomers in any proportions, including racemicmixtures thereof.

It will be evident to a skilled person that certain compounds of formula(I) can exist in enantiomeric forms according to the direction ofrotation of plane polarized light when passed through a sample of thecompound. Individual optical isomers as well as mixtures of such isomersin any proportions are within the scope of the invention.

As will be appreciated, structural formula (I) is merely atwo-dimensional representation of the compounds.

Separate groups of compounds, within formula (I), include those wherein

(i) one of R¹, R², R³ and R⁴ is fluoro;

(ii) two of R¹, R², R³ and R⁴ are fluoro;

(iii) R¹ is fluoro;

(iv) R² is fluoro;

(v) R³ is fluoro;

(vi) R⁴ is fluoro;

(vii) R⁵ is hydrogen;

(viii) R⁵ is C₁ -C₄ alkyl, preferably alkyl having 1, 2 or 3 carbonatoms and more preferably methyl or ethyl;

(ix) R⁶ is hydrogen;

(x) R⁶ is C₁ -C₄ alkyl, preferably alkyl having 1, 2 or 3 carbon atomsand more preferably methyl or ethyl;

(xi) R⁶ is hydroxy;

(xii) R⁵ and R⁶ together with the ring carbon form a carbonyl group;

(xiii) R⁷ is hydrogen;

(xiv) R⁷ is hydroxy;

(xv) R⁸ is hydrogen;

(xvi) R⁸ is C₁ -C₄ alkyl, preferably alkyl having 1, 2 or 3 carbon atomsand more preferably methyl, ethyl or isopropyl;

(xvii) R⁸ is cyclo(C₃ or C₄)alkyl, preferably cyclopropyl;

(xviii) R⁹ is hydrogen;

(ix) R⁹ is C₁ -C₄ alkyl, preferably alkyl having 1, 2 or 3 carbon atomsand more preferably methyl, ethyl or isopropyl;

(xx) R⁹ is cyclo(C₃ or C₄)alkyl, preferably cyclopropyl;

(xxi) R⁸ and R⁹ together with the nitrogen form a morpholino group;

(xxii) X is a bond;

(xxiii) X is methylene;

(xxiv) X is --O--;

and salts and solvates thereof.

Preferred as a class are compounds wherein the >C═O group and thebenzene ring are on opposite sides of the exo double bond, and salts andsolvates thereof.

Individual preferred compounds within formula (I) include

(E)-2-(6-fluoro-3 -methyl-1-indanylidene)acetamide;

(E)-N-cyclopropyl-2-(6-fluoro-3-methyl-1-indanylidene)acetamide;

(E)-2-(6-fluoro-3,3-dimethyl-1-indanylidene)-N-methylacetamide;

(E)-N-cyclopropyl-2-(6-fluoro-3-ethyl-1-indanylidene)acetamide;

(E)-N-cyclopropyl-2-(5,6-difluoro-1-indanylidene)acetamide;

(E)-2-(5,6-difluoro-1-indanylidene)-N-methylacetamide;

(E)-2-(5,6-difluoro-1-indanylidene)acetamide;

(E)-2-(5,7-difluoro-1-indanylidene)acetamide;

(E)-N-cyclopropyl-2-4,6-difluoro-1-indanylidene)acetamide;

(E)-2-(4,6-difluoro-1-indanylidene)-N-isopropylacetamide;

(E)-2-(4,6-difluoro-1-indanylidene)-N,N-dimethylacetamide;

(Z)-2-(4,6-difluoro-2-hydroxy-1-indanylidene)acetamide;

(E)-2-(7-fluoro-1,2,3,4-tetrahydro-1-naphthylidene)acetamide;

(E)-N-cyclopropyl-2-(7-fluoro-1,2,3,4-tetrahydro-1-naphthylidene)acetamide;

(E)-N-cyclopropyl-2-(6-fluoro-3,4-dihydro-2H-1-benzopyran-4-ylidene)acetamide;

(E)-2-(4,6-difluoro-1-indanylidene)acetamide;

(E)-2-(6-fluoro-1-indanylidene)acetamide;

(Z)-2-(6-fluoro-2-hydroxy-1-indanylidene)acetamide;

(E)-2-(6-fluoro-3,3-dimethyl-1-indanylidene)acetamide;

(E)-2-(6-fluoro-3-ethyl-1-indanylidene)-N,N-dimethylacetamide;

(E)-2-(6-fluoro-3-hydroxy-1-indanylidene)acetamide

and salts and solvates thereof.

Particularly preferred is (E)-2-(4,6-difluoro-1-indanylidene)acetamide,together with its salts and solvates.

Preferred salts and solvates are those that are pharmaceuticallyacceptable.

The present invention further provides a compound of formula (I), or apharmaceutically acceptable salt or solvate thereof, for use in themedical treatment of a mammal including a human being.

The present invention also provides the use of a compound of formula(I), or a pharmaceutically acceptable salt or solvate thereof, for themanufacture of a medicament for the medical treatment of a mammalincluding a human being.

The pharmaceutically acceptable salts include ammonium salts; alkalimetal salts, for example sodium and potassium salts; and alkaline earthmetal salts, for example magnesium and calcium salts.

Salts that are not pharmaceutically acceptable have utility in thepreparation and/or purification of the compounds themselves and/or ofthose salts thereof that are acceptable, and/or in non-therapeutic, forexample in vitro, applications.

The compounds of formula (I) together with their pharmaceuticallyacceptable salts and solvates are useful in medicine as central musclerelaxants and may thus be used in the treatment of conditions associatedwith abnormally raised skeletal muscle tone.

They are of especial value in the relaxation of skeletal muscle inspastic, hypertonic and hyperkinetic conditions. In particular, they maybe used in the treatment and symptomatic relief of exertion-inducedskeletal muscle spasm, for example, in lower back pain. They may also beused in conditions such as spinal cord injury, parkinsonism, chorea,arthritis, athetosis, status epilepticus and tetanus and especially inthe relief of muscle spasm in conditions such as spasticity, myositis,spondylitis, cerebral palsy, cerebrovascular disease and multiplesclerosis. They may also be used as pre-surgical muscle relaxants.

Compounds of formula (I) together with their pharmaceutically acceptablesalts and solvates are also useful in the treatment of conditionsassociated with a convulsive state, for example that following grandmal, petit mal, psychomotor epilepsy or focal seizure.

Compounds of formula (I) together with their pharmaceuticallyacceptable, salts and solvates are also useful in the treatment ofanxiety; as used herein, this term should be understood to includeanxiety disorders.

Anxiety disorders are defined, in the Diagnostic and Statistical Manualof Mental Disorders (Third Edition--Revised, 1987, published by theAmerican Psychiatric Association, Washington, D.C., U.S.A., see pages235 to 253), as psychiatric conditions having symptoms of anxiety andavoidance behaviour as characteristic features. Included amongst suchconditions are generalised anxiety disorder, simple phobia and panicdisorder.

Anxiety also occurs as a symptom associated with other psychiatricdisorders, for example obsessive compulsive disorder, post-traumaticstress disorder, schizophrenia, mood disorders and major depressivedisorders, and with organic clinical conditions such as Parkinson'sdisease, multiple sclerosis and other physically incapacitatingdisorders.

Compounds of formula (I) together with their pharmaceutically acceptablesalts and solvates are also useful in the treatment of pain, for examplethat associated with inflammation and/or trauma, and have utility asmild and strong analgesics.

Compounds of formula (I) together with their pharmaceutically acceptablesalts and solvates are also useful in the treatment of inflammatoryconditions including inflammatory arthritic conditions, for examplerheumatoid arthritis, rheumatoid spondylitis, osteoarthritis and goutyarthritis; and non-articular inflammatory conditions, for exampleherniated/ruptured/prolapsed intervertebral disk syndrome, bursitis,tendinitis, tenosynovitis, fibromyalgia syndrome and other inflammatoryconditions associated with ligamentous sprain and regionalmusculoskeletal strain. It is particularly notable that they are lessulcerogenic than other anti-inflammatory agents such as ibuprofen,naproxen and aspirin.

The present invention thus also provides a method for the treatment of

a) a condition associated with abnormally raised skeletal muscle tone;

b) a condition associated with a convulsive state;

c) anxiety;

d) pain; or

e) an inflammatory condition

in a mammal including a human being, the method comprising administeringthereto a therapeutically effective amount of a compound of formula (I)or a pharmaceutically acceptable salt or solvate thereof

The compounds of formula (I) and their pharmaceutically acceptable saltsand solvates may be administered concomitantly with other therapeuticagents for the treatment of the above-recited conditions. For conditionsassociated with abnormally raised skeletal muscle tone, such otheragents include analgesics such as codeine, acetaminophen, phenacetin andibuprofen. For inflammatory conditions (for example, arthritis) and/orpain, such other agents include analgesics, such as codeine, oxycodone,acetaminophen, phenacetin and ibuprofen; anti-arthritics, such asmethotrexate and azathioprine; and decongestants, such as ephedrine andpseudoephedrine.

The compound, salt or solvate (hereinafter together referred to as theactive ingredient) may be administered by any suitable route includingoral, rectal, nasal, topical (including buccal and sublingual), vaginal,parenteral (including subcutaneous, intramuscular, intravenous andintradermal) and transdermal. It will be appreciated that the preferredroute will be determined by, for example, the condition and age of therecipient and the identity of the condition to be treated.

The amount required of the active ingredient depends upon a number offactors including the identity of the condition and its severity, theidentity of the recipient and the route of administration and willultimately be at the discretion of the attendant physician.

In general, for each of the above-recited conditions, a suitable dose ofthe active ingredient (estimated as the parent compound) is in the rangeof 0.05 to 100 mg per kilogram body weight of the recipient per day,preferably in the range of 0.1 to 50 mg per kilogram body weight perday, most preferably in the range of 0.5 to 20 mg per kilogram bodyweight per day and optimally 1 to 10 mg per kilogram body weight perday. The desired dose is preferably presented as two, three, four, five,six or more sub-doses administered at appropriate intervals throughoutthe day.

While it is possible for the active ingredient to be administered aloneit is preferable to present it as a pharmaceutical compositioncomprising an active ingredient, as defined above, together with anacceptable carrier therefor. Each carrier must be "acceptable" in thesense of being compatible with the other ingredients of the compositionand not injurious to the recipient.

The compositions include those suitable for oral, rectal, nasal, topical(including buccal and sublingual), vaginal, parenteral (includingsubcutaneous, intramuscular, intravenous and intradermal) or transdermaladministration. The compositions may conveniently be presented in unitdosage form and may be prepared by any methods well known in the art ofpharmacy. Such methods include the step of bringing into association theactive ingredient with the carrier which constitutes one or moreaccessory ingredients. In general, the compositions are prepared byuniformly and intimately bringing into association the active ingredientwith liquid carriers or finely divided solid carriers or both, and thenif necessary shaping the product.

Compositions of the present invention suitable for oral administrationmay be presented as discrete units such as capsules, cachets or tabletseach containing a predetermined amount of the active ingredient; as apowder or granules; as a solution or suspension in an aqueous ornon-aqueous liquid; or as an oil-in-water liquid emulsion or awater-in-oil liquid emulsion. The active ingredient may also bepresented as a bolus, electuary or paste.

A tablet may be made by compression or molding, optionally with one ormore accessory ingredients. Compressed tablets may be prepared bycompressing in a suitable machine the active ingredient in afree-flowing form such as a powder or granules, optionally mixed with abinder (e.g. povidone, gelatin, hydroxypropylmethyl cellulose),lubricant, inert diluent, preservative, disintegrant (e.g. sodium starchglycollate, cross-linked povidone, cross-linked sodium carboxymethylcellulose), surface-active or dispersing agent. Molded tablets may bemade by molding in a suitable machine a mixture of the powdered compoundmoistened with an inert liquid diluent. The tablets may optionally becoated or scored and may be formulated so as to provide slow orcontrolled release of the active ingredient therein using, for example,hydroxypropylmethyl cellulose in varying proportions to provide thedesired release profile. Tablets may optionally be provided with anenteric coating, to provide release in parts of the gut other than thestomach.

Compositions suitable for oral use as described above may also includebuffering agents designed to neutralize stomach acidity. Such buffersmay be chosen from a variety of organic or inorganic agents such as weakacids or bases admixed with their conjugated salts.

Compositions suitable for topical administration in the mouth includelozenges comprising the active ingredient in a flavored basis, usuallysucrose and acacia or tragacanth; pastilles comprising the activeingredient in an inert basis such as gelatin and glycerin, or sucroseand acacia; and mouthwashes comprising the active ingredient in asuitable liquid carrier.

Compositions for rectal administration may be presented as a suppositorywith a suitable base comprising for example cocoa butter or asalicylate.

Compositions suitable for vaginal administration may be presented aspessaries, tampons, creams, gels, pastes, foams or spray formulationscontaining in addition to the active ingredient such carriers as areknown in the art to be appropriate.

Compositions suitable for parenteral administration include aqueous andnon-aqueous isotonic sterile injection solutions which may containanti-oxidants, buffers, bacteriostats and solutes which render thecompositions isotonic with the blood of the intended recipient; andaqueous and non-aqueous sterile suspensions which may include suspendingagents and thickening agents, as liposomes or other microparticulatesystems which are designed to target the compounds to blood componentsor one or more organs. The compositions may be presented in unit-dose ormulti-dose sealed containers, for example, ampoules and vials, and maybe stored in a freeze-dried (lyophilized) condition requiring only theaddition of the sterile liquid carrier, for example water forinjections, immediately prior to use. Extemporaneous injection solutionsand suspensions may be prepared from sterile powders, granules andtablets of the kind previously described.

Compositions suitable for transdermal administration may be presented asdiscrete patches adapted to remain in intimate contact with theepidermis of the recipient for a prolonged period of time. Such patchessuitably contain the active ingredient as an optionally buffered,aqueous solution of, for example, 0.1 to 0.2M concentration with respectto the said compound. As one particular possibility, the activeingredient may be delivered from the patch by iontophoresis as generallydescribed in Pharmaceutical Research, 3(6), 318 (1986).

Preferred unit dosage compositions are those containing a daily dose orunit, daily sub-dose, or an appropriate fraction thereof, of activeingredient, for example 1 to 1500 mg, preferably 5 to 1000 mg and mostpreferably 10 to 700 mg of active ingredient, estimated as the parentcompound.

It should be understood that in addition to the ingredients particularlymentioned above the compositions of this invention may include otheragents conventional in the art having regard to the type of compositionin question, for example, those suitable for oral administration mayinclude such further agents as sweeteners, thickeners and flavouringagents.

The present invention thus also provides a pharmaceutical compositioncomprising a compound of formula (I) or a pharmaceutically acceptablesalt or solvate thereof together with an acceptable carrier therefor.

The compounds of formula (I) and their salts and solvates may beprepared in any manner known in the art for the preparation of compoundsof analogous structure, for example, in accordance with the presentinvention, by those methods hereinafter described.

The compounds, salts and solvates may thus be prepared by a processwhich comprises:

reacting a compound of formula (II) ##STR3## wherein R¹ to R⁷ and X areas hereinbefore defined and Z is a leaving group with an amine NR⁸ R⁹ ora suitable derivative thereof. Suitable leaving groups include halogenatoms such as chlorine or bromine, activated esters(e.g.,N-hydroxysuccinimide, pentafluoro- phenyl, nitrophenyl,1-hydroxybenzotriazole), mixed anhydrides(e.g., ethoxycarbonyloxy) orC₁₋₆ alkoxy (for example, ethoxy). The reaction is suitably carried outin an inert organic solvent(e.g., dichloromethane) at a temperature ofabout -20° C. -120° C., and conveniently at about 0° to 25° C. Suitablederivatives of the amine include hydrated and hydrochloride derivatives,e.g. NH₄ OH, NH₄ Cl.

When R⁸ and R⁹ are H the compounds of formula (I) can be prepared byreacting compounds of formula (II) wherein X is a halogen atom such aschlorine or bromine with the amine in hydrated form, e.g. NH₄ OH, in asuitable organic solvent(e.g., dichloromethane) at a temperature ofabout 0° C. to 25° C.

Compounds of formula(I) wherein R⁶ or R⁷ are hydroxy can be prepared byreacting compounds of formula (II) wherein X is C₁₋₆ alkoxy, forexample, ethoxy, and the hydroxy group is suitably protected, forexample by SiMe₂ t--Bu, with the amine present as the hydrochloride,e.g. NH₄ Cl in the presence of Me₃ Al under neutral conditions followedby deprotection under neutral conditions with, for example, pyridiniumpara-toulenesulfonate(PPTS).

Alternatively, compounds of formula (I) wherein R⁶ or R⁷ are hydroxy canbe prepared from compounds of formula (I) wherein R⁶ or R⁷ are H byhalogenation with, for example, N-bromosuccinamide(NBS) followed byhydrolysis with, for example, silver carbonate (AgCO₃). Compounds offormula (I) wherein the R⁶ or R⁷ is/are allylic hydroxy can be preparedfrom compounds of formula (I) wherein R⁶ or R⁷ are H by oxidation with,for example selenium dioxide.

Compounds of formula (II) wherein Z is a halogen atom can be preparedfrom compounds of formula (III) ##STR4## wherein R¹ -R⁷ and X are ashereinbefore defined by reaction with a halogenating agent(e.g., oxalylchloride, or thionyl chloride) in a suitable organic solvent(e.g.,benzene, toluene, dichloromethane) optionally in the presense of acatalyst(for example DMF)at a temperature of about -20° C. to the refluxtemperature.

Compounds of formula (II) wherein Z is alkoxy(e.g., ethoxy) can beprepared from compounds of formula (III) by reaction with a suitablepolar solvent (e.g., an organic alcohol such as ethanol) optionally inthe presence of a catalytic amount of an acid(e.g., tosic acid) at atemperature of about 0° C. to the reflux temperature.

Compounds of formula (II) wherein Z is an activated ester(as describedhereinbefore) can be prepared from compounds of formula (III) byreaction with the phenol or N-hydroxy compound and a carbodiimide(e.g.,dicyclohexylcarbodiimide or1-(3-dimethylaminopropyl)-3-ethylcarbodiimide) in a solvent such asdimethylformamide(DMF) or dichloromethane at 0° C. to 50° C.

Compounds of formula (III) can be prepared by dehydration of compoundsof formula (IV) (IV) ##STR5## wherein R¹ -R⁷ and X are as hereinbeforedefined by reaction with an appropriate dehydrating agent(e.g., an acidsuch as trifluoroacetic acid) in a suitable organic solvent(e.g.,dichloromethane) at a temperature of about -20° C. to the refluxtemperature.

Compounds of formula (IV) can be prepared by saponification of thecorresponding C₁₋₆ alkyl ester, with a base(e.g., sodium hydroxide) in asuitable polar solvent(e.g., ethanol) at a temperature of about 0° C. tothe reflux temperature or with an aqueous acid(e.g., hydrochloric acid)at a temperature of about 0° C. to the reflux temperature.

Esters of compounds of formula (IV) having R⁶ or R⁷ as protected hydroxygroups, for example, by SiMe₂ t-Bu, can be dehydrated under neutralconditions(e.g., Martin Sulfurane, bisα,α-bis(trifluoromethyl)benzenemethanolato!-diphenylsulfur) to give thecorresponding protected hydroxy compounds of formula (II) and wherein Zis C₁₋₆ alkoxy(e.g., ethoxy).

The esters of compounds of formula (IV) can be prepared from compoundsof formula (V) ##STR6## wherein R¹ -R⁷ and X are as hereinbefore definedby reaction with hal CH₂ CO₂ R wherein hal is a halogen atom such aschlorine, bromine, or iodine(preferably bromine), and R is C₁₋₆ alkyl,(eg ethyl) in the presence of a metal(e.g., zinc, preferably activatedzinc) and a catalytic amount of halogen(e.g., iodine) in a suitableorganic solvent(e.g., ethyl ether, benzene) at a temperature of about 0°C. to the reflux temperature or by reaction with the lithium salt ofethyl acetate in a suitable solvent(e.g., tetrahydrofuran) at atemperature between -100° C. to room temperature(e.g., -80° C. to -70°C.).

Compounds of formula(V) having R⁶ or R⁷ as protected hydroxy groups asdefined above can be prepared from the corresponding unprotected hydroxycompound of formula (V) by suitable protection under neutral conditionswith, for example, t-butyl-di-methylsilyl chloride in the presence of abase such as imidazole.

Compounds of formula(V) having R⁶ or R⁷ as hydroxy can be prepared fromthe corresponding halogen(e.g., bromo) compound by hydrolysis underneutral conditions with, for example, silver carbonate(AgCO₃).

Compounds of formula(V) having R⁶ or R⁷ as allylic alkyl(e.g., methyl)can be prepared from the corresponding compounds of formula(V) whereinR⁶ and/or R⁷ are H by reaction with a base(e.g., sodium hydride)followed by alkylation with, for example, methyl iodide(MeI).

Compounds of formula (V) can be prepared from compounds of formula (VI)##STR7## wherein R¹ -R⁷, X and Z are as hereinbefore defined, preferablyZ is a halogen atom such as chlorine by cyclization in the presence of alewis acid(e.g., aluminum chloride) in a suitable solvent(e.g.,dichloromethane) at a temperature of about 0° C. to the refluxtemperature.

Compounds of formula (VI) wherein Z is a halogen atom(e.g., chlorine, orbromine) can be prepared from the corresponding carboxylic acid byreaction with a halogenating agent(e.g., oxalyl chloride or thionylchloride) either neat or in a suitable organic solvent(e.g. methylenechloride or N,N-dimethylformamide) at a temperature of about 0° C. tothe reflux temperature.

Compounds of formula (VI) wherein Z is alkoxy(e.g., ethoxy) can beprepared from compounds of formula (VII) ##STR8## wherein R¹ -R⁷ and Xare as hereinbefore defined by reaction with a suitable organic alcohol(e.g., ethanol) optionally in the presence of a catalytic amount of anacid(e.g., tosic acid) at a temperature of about 0° C. to the refluxtemperature.

The carboxylic acids can be prepared by saponification of thecorresponding C₁₋₆ alkyl ester compounds with a base(e.g., sodiumhydroxide) in a suitable polar solvent(e.g., water or ethanol) at atemperature of about 0° C. to the reflux temperature or with an aqueousacid (e.g., hydrochloric acid) at a temperature of about 0° C. to thereflux temperature.

The carboxyclic acids wherein X is other than oxygen can be preparedfrom compounds of formula (VIII) ##STR9## wherein R and R¹ -R⁶ are ashereinbefore defined and n is 0 or 1 by mono de-esterification withstrong base(e.g., aqueous potassium hydroxide) at the refluxtemperature.

Compounds of formula (VII) can be prepared by reacting a compound offormula (IX) with a compound of formula (X) ##STR10## wherein R, R¹ -R⁶and n are as hereinbefore defined and Hal is Cl, Br or I preferably Brin an organic solvent(e.g., anhydrous diethyl ether) and optionally inthe presence of a copper halide(e.g., copper (I) iodide) at atemperature of between -50° C. to the reflux temperature.

Compounds of formula (IX) can be prepared by reacting a compound offormula (XI) with a compound of formula (XII) ##STR11## wherein R, R⁵and R⁶ are as hereinbefore defined and m is 1 or 2 in an organicsolvent(e.g., ethyl ether or dichloromethane) at a temperature ofbetween room temperature and the reflux temperature.

Compounds of formula (X) can be prepared from the correspondinghalo(e.g., bromo, chloro) compound by standard techniques well known tothose skilled in the art. The halo compounds themselves can be obtainedcommercially or or prepared by methods well known to those skilled inthe art or obtainable from the chemical literature.

Alternatively, compounds of formula (IX) can be prepared according tothe procedure of E. L. Eliel, R. O. Hutchins, and Sr. M. Knoeber,Organic Synthesis Coll. Vol. VI, 442, 1988 with the appropriatemodifications readily apparent to those skilled in the art.

Compounds of formula (XI), and (XII) can be obtained commercially or bytechniques well known to those skilled in the art or readily obtainablefrom the chemical literature.

Alternatively the esters can be prepared from compounds of formula(XIII) ##STR12## wherein R, R¹ -R⁴, R⁶ and R⁷ are as hereinbeforedefined by reduction of the double bond, e.g., by catalytic reductionwith e.g., platinum oxide(PtO₂) and hydrogen, in a suitable organicsolvent(e.g., ethanol) at a temperature of about 20° C. to 60° C.

When X is oxygen, the esters can be prepared by reacting a compound offormula (XIV) with a compound of formula (XV) ##STR13## wherein R, R¹-R⁶ and Z are as hereinbefore defined, in a suitable organic solvent inthe presence of a base(e.g., sodium hydride).

Compounds of formula (XIV) and (XV) can be obtained commercially or bymethods well known to those skilled in the art or readily obtainablefrom the chemical literature.

Compounds of formula (XIII) can be prepared from compounds of formula(XVI) ##STR14## wherein R¹ -R⁴, R⁶ and R⁷ are as hereinbefore defined byesterification with an appropriate organic alcohol(e.g., ethanol)optionally in the presense of a catalytic amount of an acid(e.g., HCl,tosic acid, thionyl chloride)at a temperature of about 20° C. to 60° C.

Compounds of formula (XVI) can also be used to directly prepare thecorresponding unsaturated acid by reduction of the double bond, e.g., bycatalytic reduction with e.g., palladium or platinum oxide(PtO₂) andhydrogen, in a suitable organic solvent(e.g., ethanol) at a temperatureof about 0° C. to the reflux temperature.

Compounds of formula (XVI) can be prepared from compounds of formula(XVII) ##STR15## wherein R¹ -R⁴ and R⁶ are as hereinbefore defined byreaction with HOOCCHR⁷ COOH in an organic base(e.g., pyridine)optionally in an organic solvent(e.g., dichloromethane) optionally in acatalytic amount of a base(e.g., piperidine) at a temperature of about0° C. to the reflux temperature.

Compounds of formula (XVII) and HOOCCHR⁷ COOH can be obtainedcommercially or by methods well known to those skilled in the art orreadily obtainable from the chemical literature.

Alternatively, compounds of formula (I) can be prepared by reacting R⁸R⁹ NCOCH₂ PO(OR)₂ (wherein R,R⁸,R⁹ are as hereinbefore defined) with abase (e.g., NaH) in a suitable organic solvent (e.g., THF or DMSO) andreacting the resultant anionic species with a compound of formula (VI)or (VIa) respectively at a temperature of about 0° C. to the refluxtemperature. The addition of a anionic stablizing reagent (e.g.,potassium hexamethyldisilizane or a crown ether (e.g., 15-crown-5) canaid the reaction.

The compound R⁸ R⁹ NCOCH₂ PO(OR)₂ can, depending on R, R⁸ and R⁹ beobtained commercially or by methods well known to those skilled in theart or readily obtainable from the chemical literature. Alternatively,these compounds can be prepared by reacting the appropriate R⁸ R⁹ NCOCH₂Z (wherein Z is as hereinbefore defined) with the appropriate P(OR)₃ ina suitable organic solvent (e.g., THF) at a temperature of about 0° C.to 50° C.

The compound R⁸ R⁹ NCOCH₂ Z can be prepared by reacting the appropriateR⁸ R⁹ NH with ZCH₂ COZ in a suitable organic solvent (e.g., diethylether) at a temperature of about 0° C. to the reflux temperature.

The compound R⁸ R⁹ NH can be obtained commercially or by methods wellknown to those skilled in the art of preparing amines or readilyobtainable from the chemical literature. The compound ZCH₂ COZ can beobtained commercially or by methods well known to those skilled in theart of preparing such compounds or readily obtainable from the chemicalliterature.

Alternatively, compounds of formula (I) can be prepared by reacting R⁸R⁹ NCOCH₂ P(⁺)(Ph)₃ Cl(⁻)(wherein R⁸, R⁹ and Z are as hereinbeforedefined and Ph is phenyl) with a suitable base (e.g., NaH) in a suitableorganic solvent (e.g., dimethoxyethane) at a temperature of about 0° C.to 50° C., and reacting the resultant anionic species with a compound offormula (V) at a temperature of about 0° C. to the reflux temperature.

The compound R⁸ R⁹ NCOCH₂ P(⁺)(Ph)₃ Cl(⁻) can be prepared by reactingthe appropriate R⁸ R⁴ NCOCH₂ Z with about a 50% molar excess of P(Ph)₃(triphenylphosphine) in a suitable organic solvent (e.g., THF) at atemperature of about 20° C. to the reflux temperature.

R⁸ R⁹ NCOCH₂ Z can be prepared as defined hereinbefore.

Alternatively, compounds of formula (I) can also be prepared directlyfrom compounds of formula (III) by reaction with a suitable couplingreagent (e.g.,dicyclohexylcarbodiimide (DCC) or ethyl chloroformate)followed by reaction of the activated ester thus formed with theappropriate amine, HNR⁸ R⁹.

Alternatively, compounds of formula (I) wherein R⁵ is hydrogen and R⁶ ishydroxy can be prepared from compounds of formula (I) wherein R⁵ and R⁶together form a carbonyl group by reduction of this carbonyl group usinga suitable reducing agent, e.g. sodium borohydride in a suitable solventsuch as an alkanol (e.g. ethanol).

The compounds of formula (I) as well as any of the intermediates used inthe preparation of these compounds can be effected with one or more ofthe following optional conversions:

(i) converting a compound of formula (I) or intermediates thereof soformed into salts thereof;

(ii) when a salt of a compound of formula (I) or an intermediate thereofis formed, converting the said salt into a compound of formula (I) or anintermediate thereof.

The following Examples illustrate the present invention but should notbe construed as a limitation to the scope thereof.

EXAMPLE 1 Preparation of (E)-2-(6-Fluoro-1-indanylidene)acetamide

a) Preparation of 3-(4-Fluorophenyl)propionic Acid

A mixture of 4-fluorocinnamic acid (300.0 g, 1.8 mol, Aldrich) and 5%palladium on carbon (9.0 g) in ethanol (3 L) was hydrogenated atatmospheric pressure and room temperature for 4.5 h. The mixture wasfiltered through Celite (diatomaceous earth) and the filtrate wasconcentrated in vacuo to give 275.1 g (91%) of3-(4-fluorophenyl)propionic acid as a white solid: m.p., 86°-88° C.;

b) Preparation of 3-(4-Fluorophenyl)propionyl Chloride

A mixture of 3-(4-fluorophenyl)propionic acid (275.1 g, 1.6 mol) andthionyl chloride (300 mL, 4.1 mol) was heated to reflux for 3 h, cooledto room temperature and distilled under aspirator vacuum to give 287.6 g(96%) of 3-(4-fluorophenyl)propionyl chloride as a pale pink oil, b.p.,120°-122° C./15 mm Hg:

c) Preparation of 6-Fluoro-1-indanone

A solution of 3-(4-fluorophenyl)propionyl chloride (287.6 g, 1.5 mol) indichloromethane (1.4 L) was added dropwise during 3 h to an ice-cold,mechanically stirred suspension of aluminum chloride (226.0 g, 1.7 mol,Aldrich) in dichloromethane (2.2 L) under nitrogen. The resultingyellowish-black solution was refluxed for 5 h and allowed to cool toroom temperature. The solution was washed successively with water (2 L),1N sodium hydroxide (2 L), water (2 L) and brine (2 L). The organiclayer was dried over anhydrous sodium sulfate, filtered and concentratedto a tan solid (229.1 g, 99%). The solid was recrystallized fromdichloromethane-hexane to give 215.7 g (93%) of 6-fluoro-1-indanone asoff-white crystals, m.p., 57°-59° C.;

d) Preparation of Ethyl 2-(6-Fluoro-1-hydroxy-1-indanyl)acetate

(i) A mixture of 6-fluoro-1-indanone (5.0 g, 33.3 mmol), ethylbromoacetate (8.3 g, 50.0 mmol, Aldrich), activated zinc powder (3.2 g,50.0 mmol, Mallinckrodt; Org. Synth., Coll. Vol. 6, 290, 1988) and a fewcrystals of iodine in diethyl ether-benzene (1:1, 100 mL) was heated atreflux under nitrogen for 24 h. The mixture was filtered and thefiltrate was concentrated in vacuo. The residue in diethyl ether wasvigorously stirred with excess dilute ammonium hydroxide, dried andconcentrated to give ethyl 2-(6-fluoro-1-hydroxy-1-indanyl)acetate as anamber oil (7.6 g, 97%);

(ii) Ethyl acetate (1.8 g, 20 mmol) was added dropwise to a stirred,chilled (dry ice-acetone bath) IN solution of lithiumbis(trimethylsilyl)amide in tetrahydrofuran (20 mL, Aldrich) undernitrogen. After 15 min, a solution of 6-fluoro-1-indanone (3.0 g, 20mmol) in tetrahydrofuran (20 mL) was added dropwise and the resultingmixture was stirred for 1 h (dry ice-acetone bath). A IN solution ofhydrochloric acid (20 mL) was added and the mixture was allowed to warmto room temperature. The organic phase was separated, dried overanhydrous sodium sulfate, filtered and concentrated to a pale yellow oil(5.3 g). The mixture was chromatographed on Silica Gel 60 (silica gel)using a linear gradient of dichloromethane- hexanes (1:1) todichloromethane as eluent. The fractions containing only ethyl2-(6fluoro-1-hydroxy-1-indanyl)acetate were combined and concentrated invacuo to give 3.1 g (65%) of a colorless oil:

e) Preparation of 2-(6-Fluoro-1-hydroxy-1-indanyl)acetic Acid

A mixture of ethyl 2-(6-fluoro-1-hydroxy-1-indanyl)acetate (44.0 g, 0.18mol), 1N sodium hydroxide (180 mL) and absolute ethanol (280 mL) wasstirred for 18 h at room temperature. The mixture was concentrated invacuo, diluted with H₂ O and extracted with diethyl ether. The aqueousphase was acidified (pH 3) with dilute hydrochloric acid and extractedwith diethyl ether. The diethyl ether layer was washed with brine, driedover sodium sulfate, filtered and concentrated in vacuo to give2-(6-fluoro-1-hydroxy-1-indanyl)acetic acid as an amber oil (37.7 g,100%; Note: This compound spontaneously dehydrated upon standing at roomtemperature to a mixture of olefins unless immediately reacted withtrifluoroacetic acid);

f) Preparation of Lithium 2-(6-Fluoro-1-hydroxy-1-indanyl)acetate

A mixture of ethyl 2-(6-fluoro-1-hydroxy-1-indanyl)acetate (2.0 g. 8.4mmol), 1N lithium hydroxide (8.4 mL) and absolute ethanol (13.0 mL) wasstirred for 18 h at room temperature. The mixture was concentrated invacuo, diluted with H₂ O and extracted with diethyl ether. The aqueousphase was concentrated in vacuo, diluted with toluene (100 mL) andconcentrated in vacuo to give lithium2-(6-fluoro-1-hydroxy-1-indanyl)acetate as a white solid (1.4 g, 77%);

g) Preparation of (E)-2-(6-Fluoro-1-indanylidene)acetic Acid

Trifluoroacetic acid (1.5 mL) was added to a stirred, chilled(ice-methanol bath) suspension of lithium2-(6-fluoro-1-hydroxy-1-indanyl)acetate (0.5 g, 2.3 mmol) indichloromethane (13.5 mL). After 15 min, the mixture was concentrated invacuo and the resulting white solid was recrystallized from aqueousacetone to give (E)-2-(6-fluoro-1-indanylidene)acetic acid as whitecrystals (0.32 g, 73%) identical to compound of Example 1i by mixedm.p., (203°-205° C.) and NMR;

h) Preparation of (E)-2-(6-Fluoro-1-indanylidene)acetic Acid

Trifluoroacetic acid (100 mL) was added to a stirred, chilled(ice-methanol bath) solution of 2-(6-Fluoro-1-hydroxy-1-indanyl)aceticacid (37.5 g, 0.18 mol) in dichloromethane (900 mL). After 15 min, themixture was concentrated in vacuo to give(E)-2-(6-fluoro-1-indanylidene)acetic acid as a yellowish-tan solid(33.0 g, 95%), m.p., 203°-205° C.;

i) Preparation of (E)-2-(6-Fluoro-1-indanylidene)acetyl Chloride

An ice-cold, stirred suspension of (E)-2-(6-fluoro-1-indanylidene)acetic acid (384 mg, 2 mmol) in benzene (10 mL) was treated with oxalylchloride (761 mg, 6 mmol) and allowed to warm to room temperature during1.5 h. The resulting yellow solution was concentrated in vacuo to give(E)-2-(6-fluoro-1-indanylidene)acetyl chloride as a pale yellow solid(421 mg, 100%), m.p., 97°-99° C.;

j) Preparation of (E)-2-(6-Fluoro-1-indanylidene)acetamide

A 29.6% aqueous ammonium hydroxide solution (17.6 mL, 134 mmol) wasadded dropwise to a stirred, chilled (ice bath) solution of(E)-2-(6-fluoro-1-indanylidene)acetyl chloride (14.1 g, 67 mmol) indichloromethane (165 mL). After an hour, the resulting white precipitatewas collected by filtration, dissolved in ethyl acetate (600 mL) andwashed with water (3×300 mL). The ethyl acetate layer was dried oversodium sulfate and concentrated in vacuo. The resulting off-white solidwas washed with hexane, giving 11.6 g (91%) of(E)-2-(6-fluoro-1-indanylidene)acetamide, m.p., 180°-183° C.;

EXAMPLE 2 Preparation of (E)-2-(6-Fluoro-1-indanylidene)acetamide

A stirred suspension of(E)-2-(6fluoro-1-indanylidene)acetic acid (0.5 g,2.6 mmol) in dichloromethane (10 mL) at -20° C. was successively treateddropwise with ethyl chloroformate (0.3 g, 2.6 mmol, Aldrich) andtriethylamine (0.3 g, 2.6 mmol, Eastman). The mixture was stirred at-20° C. for 2 h. A solution of anhydrous ammonia in dichloromethane(0.8M, 12 mL) was added Note: When aqueous ammonium hydroxide was used,the mixed anhydride was partially hydrolyzed to the acid.!, the mixturewas stirred for 16 h at room temperature, and subsequently washedsuccessively with water, sodium bicarbonate solution, water and brine.The dichloromethane layer was dried over sodium sulfate, filtered, andconcentrated in vacuo to give 0.18 g of a 6:1 mixture of(E)-2-(6-fluoro-1-indanylidene)acetamide and2-(5-fluoro-1H-inden-3-yl)acetamide.

EXAMPLE 3 Preparation of(E)-N-Ethyl-2-(6-fluoro-1-indanylidene)acetamide

This compound was prepared in an analogous manner to that of Example 5with replacement of cyclopropylamine in Example 5 with ethylamine (70 wt% in water). The chromatography solutions that contained(E)-N-Ethyl-2-(6-fluoro-1-indanylidene)acetamide were concentrated byspin evaporation in vacuo. Recrystallization of the residue fromdichloromethane-hexanes gave 1.7 g (68%) of(E)-N-ethyl-2-(6-fluoro-1-indanylidene)acetamide, m.p. 125°-127° C.;

EXAMPLE 4 Preparation of(E)-N-Cyclopropyl-2-(6-fluoro-1-indanylidene)acetamide

To an ice-cold stirred solution of (E)-2-(6-Fluoro-1-indanylidene)acetylChloride in dichloromethane (50 ml) was added cyclopropylamine (1.65 g,28.86 mmol) and the reaction was warmed to room temperature overnight.The reaction was evaporated in vacuo to a solid residue. This residuewas dissolved in ethyl acetate (300 ml), washed with water (75 ml), andthe organic layer was concentrated by spin evaporation in vacuo. Theresidue was chromatographed on silica gel using ethyl acetate-hexanes(0:1 to 1:1 gradient) as eluent. Fractions containing only the productwere combined and concentrated by spin evaporation in vacuo.Recrystallization of the residue from dichloromethane-hexanes gave 1.6 g(76%) of (E)-N-cyclopropyl-2-(6-fluoro-1-indanylidene)acetamide as awhite powdery solid, m.p. 124°-127° C.;

(E)-N-Ethyl-2-(6-fluoro-1-indanylidene)-N-methylacetamide was preparedin an analogous manner with replacement of cyclopropylamine withN-ethylmethylamine (3.5 mL, 0.025 mol, Aldrich). The residue waschromatographed on silica gel using ethyl acetate-hexanes (1:5 to 1:2gradient) as eluent. The chromatography fractions that contained(E)-N-ethyl-2-(6-fluoro-1-indanylidene)-N-methylacetamide wereconcentrated by spin evaporation in vacuo. Recrystallization of theresidue from ethyl acetate-hexanes gave 1.32 g (61%) of(E)-N-ethyl-2-(6-fluoro-1-indanylidene)-N-methylacetamide as a whitesolid, m.p. 74°-77° C.;

EXAMPLE 5 Preparation of (E)-2-(4,6 Difluoro-1-indanylidene)acetamide

a) Preparation of 3-(2,4-Difluorophenyl)propanoic Acid

A mixture of 2,4-difluorocinnamic acid (30.0 g, 0.16 mol, Aldrich ) andplatinum oxide hydrate (0.5 g, EM Scientific) in 95% ethanol (140 mL)was placed on a Parr hydrogenation apparatus. After the appropriateamount of hydrogen was taken up, the catalyst was filtered and thefiltrate was concentrated in vacuo to give 29.7 g (98%) of3-(2,4-difluorophenyl)propanoic acid as a white solid. Recrystallizationof 1.0 g from acetonitrile: water mixtures gave 0.61 g of3-(2,4-difluorophenyl)propanoic acid as a white solid: mp 104°-106° C.;NMR (DMSO-d₆); d 12.2 (br, 1H), 6.98-7.40 (m, 3H), 2.81 (t, 2H), 2.51(t, 2H).

Anal. Calcd. for C₉ H₈ F₂ O₂ (mw 186.15): C, 58.06; H, 4.33. 3. Found:C, 57.94; H, 4.36.

b) Preparation of 4,6-Difluoro-1-indanone

To a mixture of 3-(2,4-difluorophenyl) propanoic acid (28.7 g, 0.15 mol)and dimethylformamide (5 drops) at ambient temperature was addeddropwise oxalyl chloride (50 mL, Aldrich). The mixture was stirred atambient temperature for 18 h. The excess oxalyl chloride was removed bydistillation in vacuo to give 3-(2,4-difluorophenyl)propionyl chloride.A solution of the 3-(2,4-difluorophenyl)propionyl chloride indichloromethane (300 mL) was added dropwise to a mixture of aluminumchloride (23.4 g, 0.18 mol, Aldrich) in dichloromethane (300 mL) at icebath temperature. After the addition was completed, the mixture wasrefluxed for 3.5 h and allowed to come to ambient temperatureover-night. The reaction mixture was poured into ice water (I1500 mL),the two phases were separated and the aqueous phase was extracted withdichloromethane. The combined organic phase was washed successively with0.1N aqueous sodium hydroxide and saturated sodium chloride solution,dried over sodium sulfate and concentrated in vacuo to give 21.7 g ofcrude 4,6-difluoro-1-indanone. Chromatography on silica gel withhexanes: dichloromethane (3:1) as eluent gave 10.1 g of a light yellowsolid. Recrystallization of 0.5 g from acetone: water mixtures gave 0.2g of 4,6-difluoro-1-indanone as a white solid: mp 97°-99° C.; NMR(CDCl₃): d 7.02-7.27 (m, 2H), 3.12 (t, 2H), 2.76 (m, 2H).

Anal. Calcd. for C₉ H₆ F₂ O (mw 168.14): C, 64.29, H, 3.60. Found: C,64.18; H, 3.61.

c) Preparation of Ethyl 2-(4,6-Difluoro-1-hydroxy-1-indanyl)acetate

A mixture of 4,6-difluoro-1-indanone (12.6 g, 0.08 mol), ethylbromoacetate (19.0 g, 0.11 mol, Aldrich), activated zinc powder (7.5 g,0.11 mol, Aldrich; Org. Syn., Coll. Vol. 6, 290, 1988) and a fewcrystals of iodine in diethyl ether:toluene (1:1, 300 mL) was heated at30°-35° C. under a nitrogen atmosphere for 24 h. A few more crystals ofiodine were added, the temperature was adjusted to 40°-45° C., and themixture was kept at that temperature for an additional 24 h. Thereaction mixture was filtered and concentrated in vacuo. The residue wastreated with a mixture of diethyl ether (450 mL), concentrated ammoniumhydroxide (135 mL) and water (135 mL). The aqueous phase was separatedand extracted with diethyl ether. The combined organic phase was washedwith saturated aqueous sodium chloride solution, dried over sodiumsulfate, filtered and concentrated in vacuo to give 22.7 g of crudeEthyl 2-(4,6-difluoro-1- hydroxy-1-indanyl)acetate which wasChromatographed on silica gel with dichloromethane:hexanes (9:1) aseluent gave 12.7 g (66%) of a yellow oil; NMR (CDCl₃): d 6.67-6.88 (m,2H), 4.22 (q, 2H), 3.02 (m, 1H), 2.75 (2 m's, 3H), 2.31 (m, 2H), 1.28(t, 3H).

Anal. Calcd. for C₁₃ H₁₄ F₂ O₃ (mw 256.24): C, 60.93; H, 5.51. Found: C,60.68; H, 5.50.

d) Preparation of 2-(4,6-difluoro-1-hydroxy-1-indanyl)acetic Acid

A mixture of ethyl 2-(4,6-difluoro-1-hydroxy-1-indanyl)acetate (12.0 g0.047 mol) and 1.0N sodium hydroxide (48 mL, 0.048 mol, UniversalScientific Supply Co.) in ethanol (75 mL) was stirred for 18 h atambient temperature. The reaction mixture was concentrated in vacuo,diluted with water and washed with diethyl ether. The aqueous phase wasneutralized with 1.0N hydrochloric acid (48 mL, 0.048 mol, UniversalScientific Supply Co.) and extracted with diethyl ether. The diethylether extract was dried over sodium sulfate, filtered and concentratedin vacuo to give a quantitative yield of crude2-(4,6-difluoro-1-hydroxy-1-indanyl)acetic acid. This material was usedimmediately without further purification.

e) Preparation of (E)-2-(4,6-difluoro-1-indanylidene)acetic Acid

Trifluoroacetic acid (39.9 g, 0.35 mol) was added dropwise to a stirred,chilled (ice-methanol bath) mixture of2-(4,6-difluoro-1-hydroxy-1-indanyl)acetic acid (11.3 g, 0.05 mol) indichloromethane (250 mL). After 35 min. the mixture was concentrated invacuo. Dichloromethane was added to the residue and the mixture wasconcentrated in vacuo. This procedure was repeated once more to give 6.4g of crude (E)-2-(4,6- difluoro-1-indanylidene) acetic acid.Recrystallization of 0.9 g from acetone: water mixtures gave 0.15 g of(E)-2-(4,6-difluoro-1-indanylidene) acetic acid as a white solid: mp238°-239° C.; NMR (DMSO-d₆): d12.25 (br, 1H), 7.23-7.65 (m, 2H), 6.46(t, 1H), 3.20-3.28, 2.97-3.20(2 m's, 4H); steady-state nOe: irradiationat 6.46 d, observed 21.6% nOe at 7.63 d.

Anal. Calcd. for C₁₁ H₈ F₂ O₂ (mw 210.17): C, 62.86; H, 3.84. Found: C,62.76; H, 3.86.

f) Preparation of (E)-2-(4,6-difluoro-1-indanylidene)acetyl Chloride

A suspension of (E)-2-(4,6difluoro-1-indanylidene)acetic Acid (5.49 g,0.026 mol) in a mixture of dichloromethane: dimethylformamide (50 mL: 5drops) was treated with oxalyl chloride (6.6 g 0.052 mol, Aldrich) andallowed to stir at ambient temperature for 18 h. The resulting solutionwas concentrated in vacuo and the residue used without furtherpurification.

g) Preparation of (E)-2-(4,6-difluoro-1-indanylidene)acetamide

A 30% aqueous ammonium hydroxide solution (1.7 mL, 0.026 mol) was addeddropwise to a stirred, chilled (ice bath) solution of(E)-2-(4,6-difluoro-1-indanylidene)acetyl chloride (2.97 g, 0.013 mol)in dichloromethane (50 mL). After 4.5 h the mixture was concentrated invacuo and the residue was partitioned between 5% aqueous sodiumbicarbonate solution and ethyl acetate. The ethyl acetate solution waswashed with saturated aqueous sodium chloride, dried over sodiumsulfate, filtered and concentrated in vacuo Chromatography on silica gelwith ethyl acetate: hexanes (7:3)as eluent and trituration of theresulting solid with pentane gave 1.63 g (60%) of(E)-2-(4,6difluoro-1-indanylidene)acetamide as a white solid: mp178°-180° C.; NMR (DMSO-d₆): d 6.94-7.45 (m, 4H), 6.46 (s, 1H),2.94-3.00, 3.21-3.27 (2 m's, 4H); steady-state nOe: irradiation at 6.46d, observed 19% nOe at 7.26 d.

Anal. Calcd. for C₁₁ H₉ F₂ NO (mw 209.19): C, 63.15; H, 4.34; N, 6.70.Found: C, 63.07; H, 4.36; N, 6.67.

h) Preparation of (E)-2-(4-chloro-1-indanylidene)acetic Acid

Trifluoroacetic acid (25.1 mL) was added to a stirred, chilled(ice-methanol bath) solution of 2-(4-chloro-1-hydroxy-1-indanyl)aceticacid (10.4 g, 0.05 mol) in dichloromethane (230 mL). After 30 min, themixture was concentrated in vacuo. Dichloromethane was added to theresidue and the mixture was concentrated in vacuo to give 6.5 g (68%) ofa white solid. Recrystallization of 0.98 g from acetonitrile: 2-propanolmixtures gave 0.62 g of a white solid: m.p., 233°-234° C.; NMR(DMSO-d₆): d12.15 (br, 1H, COOH), 7.30-7.81 (m, 3H, Ar), 6.41 (s, 1H,═CH), 3.00-3.06, 3.19-3.22 (2m's, 4H, 2×CH₂), steady-state nOe;irradiation at 6.41 d, observed 19.7% nOe at 7.79.

i) Preparation of (E)-2-(4-chloro-1-indanylidene) acetyl Chloride

A suspension of (E)-2-(4-chloro-1-indanylidene)acetic acid (5.5 g, 0.03mol) in a mixture of dimethylformamide: dichloromethane (5 drops: 50 mL)was treated with oxalyl chloride (6.6 g, 0.05 mol) and allowed to stirat room temperature for 18 h. The resulting solution was concentrated invacuo and the residue used without further purification.

j) Preparation of (E)-2-(4-chloro-1-indanylidene)-N-cyclopropylacetamide

An ice cold solution of (E)-2-(4-choro-1-indanylidene)acetyl chloride(2.95 g, 0.013 mol ) in dichloromethane (30 mL) was treated withcyclopropylamine (1.48 g, 0.026 mol, Aldrich) and the mixture wasstirred for 4 h. The mixture was concentrated in vacuo and the residuewas taken up in a mixture of ethyl acetate and 5% aqueous sodiumbicarbonate. The ethyl acetate phase was washed with 5% aqueous sodiumbicarbonate, saturated aqueous NaCl and dried (Na₂ SO₄). Filtration andconcentration gave 3.5 g of crude oil product. Chromatography on Silcagel with ethyl acetate: hexanes (1:1) as eluent and trituration of theresulting solid with hexanes gave 2.46 g (76%) of(E)-2-(4-chloro-1-indanylidene)-N-cyclopropylacetamide as an off-whitesolid: m.p., 140°-142° C.; NMR (DMSO-d₆): d 8.16, d, 1H, NH), 7.29-7.51(m, 3H, Ar), 6.34 (t, 1H, ═CH), 2.93-3.07, 3.18-3.31 (2m's, 4H 2XCH₂),2.72 (m, 1H, CH), 0.62-0.72, 0.39-0.47 (2m's, 4H, 2XCH₂); steady-statenOe: irradiation at 6.34 d, observed 20.3% nOe at 7.46 d.

Anal. Calcd. for C₁₄ H₁₄ ClNO (mw 247.72): C, 67.88; H, 5.70; N 5.65.Found: C, 67.86; H, 5.74; N, 5.58.

EXAMPLE 6 Preparation of (E)-N-Cyclopropyl-2-(4,6difluoro-1-indanylidene)acetamide

An ice cold solution of (E)-2-(4,6-difluoro-1-indanylidene)acetylchloride (2.97 g, 0.013 mol) in dichloromethane (30 mL) was treated withcyclopropylamine (1.48 g, 0.026 mol, Aldrich) and the mixture wasstirred for 4 h. The mixture was concentrated in vacuo and the residuewas taken up in a mixture of ethyl acetate and 5% aqueous sodiumbicarbonate. The ethyl acetate phase was washed with 5% aqueous sodiumbicarbonate, saturated aqueous NaCl and dried (Na₂ SO₄). Chromatographyon silica gel with ethyl acetate: hexanes (1:1) as eluent andtrituration of the resulting solid with pentane gave 1.92 g (59%) of(E)-N-cyclopropyl-2-(4,6-difluoro-1-indanylidene)acetamide as a whitesolid: m.p., 156°-158° C.;

EXAMPLE 7 Preparation of (E)-2-(4-Fluoro-1-indanylidene)acetamide

a) Preparation of Ethyl 2-Fluorocinnamate

A solution of 2-fluorocinnamic acid (48.4 g, 0.29 mol, Aldrich) andthionyl chloride (5 mL) in ethanol (650 mL) was heated to reflux for 48h. The mixture was concentrated in vacuo. The residue was taken up inethyl acetate, washed successively with a 5% aqueous sodium bicarbonatesolution, water and brine, and dried (Na₂ SO₄). Filtration andconcentration gave 54.25 g (96%) of crude ethyl 2-fluorocinnamate. Thismaterial was used without further purification.

b) Preparation of Ethyl 3-(2-fluorophenyl)propionate

A mixture of ethyl 2-fluorocinnamate (29.25 g, 0.176 mol) and platinumoxide hydrate (0.25, EM Scientific) in 95% ethanol (150 mL) was placedon a Parr hydrogenation apparatus and shaken under 2-4 atm at hydrogenpressure. After the appropriate amount of hydrogen was consumed, thecatalyst was removed by filtration, and the filtrate was concentrated invacuo to give 29.39 g (99%) of crude ethyl 3-(2-fluorophenyl)propionate.This material was used without further purification.

c) Preparation of 3-(2-Fluorophenyl)propionic acid

A mixture of ethyl 3-(2-fluorophenyl)propionate (25.54 g, 0.130 mol) anda 50% aqueous solution of sodium hydroxide (30 mL) in water (130 mL) wasrefluxed for 2 h. After cooling the mixture was washed with diethylether (2×100 mL). The aqueous phase was chilled in an ice bath, and thepH was adjusted to 3 with hydrochloric acid . The white precipitatewhich formed was collected by filtration, washed repeatedly with water,and dried in a vacuum at 60° C. for 18 h to give 18.66 g (85%) of3-(2-fluorophenyl)propionic acid as a white solid; m.p., 72°-74° C. Thismaterial was used without further purification.

d) Preparation of 4-fluoro-1-indanone

To a mixture of 3-(2-fluorophenyl)propionic acid (18.64 g, 0.111 mol)and dimethylformamide (5 drops) at room temperature was added dropwiseoxalyl chloride (60 mL). The mixture was stirred at room temperatureuntil gas evolution had ceased. The excess oxalyl chloride was removedby distillation to give 3-(2-fluorophenyl)propionyl chloride. A solutionof the 3-(2-fluorophenyl)propionyl chloride in dichloromethane (230 mL)was added dropwise to a mixture of aluminum chloride (16.25 g, 0.12 mol)in dichloromethane (230 mL), and the mixture was refluxed for 3.5 h. Thereaction mixture was poured into ice water (1200 mL), and the two phaseswere separated. The dichloromethane phase was washed successively with0.1N aqueous sodium hydroxide (2×100 mL), water (200 mL), and brine (200mL), dried over sodium sulfate, filtered, and concentrated in vacuo. Theresidual oil was chromatographed on silica gel eluting withhexane:dichloromethane (9:1) to give 11.0 g of crude 4-fluoro-1-indanoneas a yellow solid. Recrystallization from acetone: water mixtures gave8.02 g (48%) of 4-fluoro-1-indanone as a pale yellow solid: m.p.,71°-72° C.; NM (DMSO-d₆): d 7.51 (m, 3H, Ar), 3.13 (t, 2H, CH₂), 2.74(t, 2H, CH₂).

Anal. Calcd. for C₉ H₇ FO (mw 150.152): C, 71.99; H, 4.70. Found: C,71.86; H, 4.79.

e) Preparation of Ethyl 2-(4-fluoro-1-hydroxy-1-indanyl)acetate

This compound was prepared in an analogous manner to that described inExample 5c for ethyl 2-(4,6-difluoro-1-hydroxy-1-indanyl)acetatesubstituting 4-fluoro-1-indanone (15.53 g, 0.103 mol) for4,6-difluoro-1-indanone. Chromatography on silica gel with ethylacetate:hexanes (19:1) as eluent gave 19.11 g (78%) of ethyl2-(4-fluoro-1-hydroxy-1-indanyl)acetate which was used without furtherpurification.

f) Preparation of 2-(4-fluoro-1-hydroxy-1-indanyl)acetic Acid

This compound was prepared in a similar manner to that described for2-(4,6-difluoro-1-hydroxy-1-indanyl)acetic acid in Example 5d bysubstituting ethyl 2-(4-fluoro-1-hydroxy-1-indanyl)acetate (17.35 g,0.0728 mol) for ethyl 2-(4,6-difluoro-1-hydroxy-1-indanyl) acetate togive a quantitative yield of crude2-(4-fluoro-1-hydroxy-1-indanyl)acetic acid. This material was usedimmediately without further purification.

g) Preparation of (E)-2-(4-fluoro-1-indanylidene)acetic Acid

This compound was prepared in an analogous manner to(E)-2-(4,6-difluoro-1-indanylidene)acetic acid in Example 5e bysubstituting 2-(4-fluoro-1-hydroxy-1-indanyl)acetic acid (14.6 g, 0.069mol) for 2-(4,6-fluoro-1-hydroxy-1-indanyl)acetic acid to give crude(E)-2-(4-fluoro-1-indanylidene)acetic acid. Recrystallization fromacetonitrile: 2-propanol mixtures gave 6.85 g (52%) of(E)-2-(4-fluoro-1-indanylidene)acetic acid as a white solid; m.p.,249°-251° C.;

h) Preparation of (E)-2-(4-fluoro-1-indanylidene)acetyl Chloride

This compound was prepared in a similar manner to(E)-2-(4,6difluoro-1-indanylidene)acetyl chloride in Example 5f bysubstituting (E)-2-(4-fluoro-1-indanylidene)acetic acid (5.77 g, 0.03mol) for (E)-2-(4,6-difluoro-1-indanylidene)acetic acid. The resultingsolution was concentrated in vacuo, and the residue was used withoutfurther purification.

i) Preparation of (E)-2-(4-fluoro-1-indanylidene)acetamide

An ice cold solution of(E)-2-(4-fluoro-1-indanylidene)acetyl chloride(2.11 g, 0.01 mol) in dichloromethane (65 mL) was treated with a 30%aqueous solution of ammonium hydroxide (2.63 ml, 0.02 mol), and themixture was stirred for 18 h. Hexane was added to the mixture, and thesolids were collected by filtration to give 1.63 g of crude product.Recrystallization from acetonitrile: water mixtures gave 1.11 g (58%) of(E)-2-(4-fluoro-1-indanylidene)-acetamide as a white solid; m.p.,198°-200° C.;

EXAMPLE 8 Preparation of(E)-2-N-cyclopropyl-(4-fluoro-1-indanylidene)acetamide

An ice cold solution of (E)-2-(4-fluoro-1-indanylidene)acetyl chloride(2.11 g, 0.010 mol) in dichloromethane (65 mL) was treated withcyclopropylamine (1.39 mL, 0.02 mol), and the mixture was stirred for 18h. Hexane was added to the mixture, and the solids were collected byfiltration and washed successively with water and hexane to give 1.22 gof crude product. Recrystallization from acetonitrile: water mixturesgave 0.83 g (36%) of(E)-2-N-cyclopropyl-(4-fluoro-1-indanylidene)acetamide as a white solid;m.p., 121°-122° C.;

EXAMPLE 9 Preparation of (E)-2-(5-fluoro-1-indanylidene)acetamide

a) Preparation of Ethyl 2-(5-fluoro-1-hydroxy-1-indanyl)acetate

This compound was prepared in an analogous manner to that described inExample 5c for ethyl 2-(4,6-difluoro-1-hydroxy-1-indanyl) acetatesubstituting 5-fluoro-1-indanone (14.77 g, 0.098 mol, Fairfield) for4,6-difluoro-1-indanone. Chromatography on silica gel with ethylacetate: hexanes (9:1 ) as eluent gave 19.56 g (83%) of analyticallypure ethyl 2-(5-fluoro-1-hydroxy-1-indanyl)acetate as a pale yellow oil;NMR (CDCl₃): d 6.88-7.30 (m, 3H, Ar), 5.30 (s, 1H, OH), 4.20 (q, 2H, CH₂CH₃), 2.66-3.08 (m, 4H, 2CH₂), 2.30 (t, 2H, CH₂ Ar), 1.28 (t, 3H, CH₃).

Anal. Calcd. for C₁₃ H₁₅ FO₃ (mw 238.25): C, 65.54; H, 6.35. Found: C,65.39; H, 6.33.

b) Preparation of 2-(5-fluoro-1-hydroxy-1-indanyl)acetic Acid

This compound was prepared in a similar manner to that described for2-(4,6-difluoro-1-hydroxy-1-indanyl)acetic acid in Example 5d bysubstituting ethyl 2-(5-fluoro-1-hydroxy-1-indanyl) acetate (19.55 g,0.082 mol) for ethyl 2-(4,6-difluoro-1-hydroxy-1-indanyl) acetate togive 14.70 g (84%) of crude 2-(5-fluoro-1-hydroxy-1-indanyl) acetic acidas a white solid. This material was used immediately without furtherpurification.

c) Preparation of (E)-2-(5-Fluoro-1-indanylidene)acetic Acid

This compound was prepared in an analogous manner to(E)-2-(4,6difluoro-1-indanylidene)acetic acid in Example 5e bysubstituting 2-(5-fluoro-1-hydroxy-1-indanyl)acetic acid(14.70 g, 0.069mol) for 2-(4,6-difluoro-1-hydroxy-1-indanyl)acetic acid.Recrystallization from acetonitrile: 2-propanol mixtures gave 9.05 g(68%) of (E)-2-(5-fluoro-1-indanylidene)acetic acid as a white solid:m.p., 240°-242° C.;

d) Preparation of (E2-(5-fluoro-1-indanylidene)acetyl Chloride

This compound was prepared in a similar manner to(E)-2-(4,6-difluoro-1-indanylidene)acetyl chloride in Example 5f bysubstituting (E)-2-(5-fluoro- I - indanylidene)acetic acid (5.77 g, 0.03mol) for (E)-2-(4,6-difluoro-1-indanylidene)acetic acid. The resultingsolution was concentrated in vacuo, and the residue was used withoutfurther purification.

e) Preparation of (E)-2-(5-fluoro-1-indanylidene)acetamide

This compound was prepared in a similar manner to that described for(E)-2-(6-fluoro-1-indanylidene)acetamide Example 1k by substituting(E)-2-(5-fluoro-1-indanylidene)acetyl chloride (3.16 g, 0.015 mol) for(E)-2-(6-fluoro-1-indanylidene)acetyl chloride. Recrystallization fromacetonitrile: water mixtures gave 1.28 g (44%) of(E)-2-(5-fluoro-1-indanylidene)acetamide as a white solid; m.p.,191°-193° C.;

EXAMPLE 10 Preparation of(E)-N-Cyclopropyl-2-(5-fluoro-1-indanylidene)acetamide

A solution of (E)-2-(5-fluoro-1-indanylidene)acetic acid (0.97 g, 0.005mol), 1-hydroxybenzotriazole (0.68 g, 0.005 mol, Fluka),cyclopropylamine (0.35 mL, 0.005 mol, Aldrich) and1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.96 g,0.005 mol, Sigma), which was added last, in dimethylformamide (15 mL)was stirred at room temperature for 18 h, and the solution wasconcentrated in vacuo. The residue was dissolved in ethyl acetate,washed successively with a 5% aqueous solution of citric acid (3×50 mL),a saturated aqueous sodium bicarbonate solution (2×50 mL) and brine, anddried over sodium sulfate. The solution was concentrated in vacuo togive crude (E)-N-cyclopropyl-2-(5-fluoro-1-indanylidene)acetamide.Chromatography on Silica gel eluting with hexane: ethyl acetate (1:1)gave 0.52 g (44%) of(E)-N-cyclopropyl-2-(5-fluoro-1-indanylidene)acetamide as a white solid:m.p., 137°-138° C.;

EXAMPLE 11 Alternative Preparation of(E)-2-(6Fluoro-1-indanylidene)acetamide

To an ice-cold stirred suspension of NaH (60% dispersion in mineral oil,12.41 g, 60.25 mmoles, Aldrich) in tetrahydrofuran (30 ml) with15-crown-5 (3.96 g, 17.98 mmoles, Aldrich) was added under N₂, diethylcarbamoylmethylphosphonate (11.7 g, 59.97 mmoles, K&K-ICN) and6-fluoro-1-indanone (9.0 g, 59.96 mmol) respectively in tetrahydrofuran(80 ml ). The mixture was allowed to warm to room temperature overnight.The mixture was poured into 200 ice-cold water and extracted with three600 ml portions of diethyl ether. One organic phase was washedsuccessively with 200 ml portions of aqueous sodium bisulfite (10%) anda saturated sodium chloride solution. The organic phase was dried overpotassium carbonate, filtered, spin evaporated in vacuo and coevaporatedwith 200 ml dichloromethane to yield a tacky solid residue. The residuewas chromatographed on Silica Gel 60 using ethyl acetate:hexane (2:1).Fractions containing (E)-2-(6-fluoro-1-indanylidene)acetamide werecombined and spin evaporated in vacuo to give 2.38 g of a yellow solid.Dilution of a dichloromethane solution of the crude material with hexanegave 2.16 g (18.8%) of (E)-2-(6-fluoro-1-indanylidene)acetamide, m.p.,178°-182° C.; NMR (DMSO-d₆); d 7.4-7.1 (m, 4H, Ar and NH), 6.88 (br s,1H, NH), 6.37 (t, 1H, J=2.54 Hz, ═CH), 3.22-3.14 (m, 2H CH₂), 2.95-2.89(m, 2H, CH₂); steady-state nOe: irradiation at d 6.37, significantobserved nOe at d 7.33-7.28.

Anal. Calcd for C₁₁ H₁₀ FNO: C, 69.10;H, 5.27; N, 7.33 Found: C, 69.01;H, 5.29; N, 7.28.

EXAMPLE 12 Preparation of(E)-N-Cyclopropyl-2-(5-fluoro-1,2,3,4-tetrahydro-1-naphthylidene)acetamide

a) Preparation of 2-(2-Fluorophenyl)ethylbromide

To a mixture of aqueous hydrobromic acid (48%, 360 mL) and concentratedsulfuric acid (103.6 mL) at room temperature was added dropwise2-(2-fluorophenyl)ethanol (250 g, 1.78 mol, Aldrich). The reactionmixture was refluxed for 7 h, poured onto 600 ml of ice and the mixturewas extracted with diethyl ether. The diethyl ether extracts were washedsuccessively with saturated sodium carbonate and brine. The organicphase was dried (MgSO₄) and concentrated in vacuo to give 359.9 g (99%)of 2-(2-fluorophenyl)-ethylbromide as a brown oil. This product was usedwithout further purification. NMR (CDCl₃ : d 7.6-6.9 (m. 4H, ArH), 3.6(t, 2H CH₂), 3.2 (t, 2H, CH₂).

b) Preparation of Diethyl 2-(2-(2-fluorophenyl)ethylmalonate

To absolute ethanol (1.5 L) at room temperature under a nitrogenatmosphere was added sodium metal (61.1 g, 2.66 mol) in small piecesover several hours. After stirring for 24 h at room temperature, themixture was warmed to 40° C., and dimethyl malonate (525.4 g, 3.28 mol)was added dropwise followed by 2-(2-fluorophenyl)ethylbromide (359.9 g,1.77 mol). The mixture was refluxed for 8 h. The crude material waspurified by vacuum distillation at 85°-130° C. and 0.60 mm Hg to give312.6 g (62%) of diethyl 2-(2-(2-fluorophenyl)ethyl)malonate as a clearoil. NMR (CDCL₃): d 7.6-7.0 (m, 4H, ArH), 4.2 (q, 4H, 2X CH₂) 3.4 (t,1H, CH), 2.6 (q, 2H, CH₂), 2.2 (t, 2H, CH₂), 1.2 (t, 6H, 2X CH₃).

c) Preparation of 2- 2-(2-Fluorophenyl)ethyl!malonic acid

A mixture of diethyl 2-(2-(2-fluorophenyl)ethyl)malonate (381.8 g, 1.35mol) and potassium hydroxide (227.3 g, 4.1 mol) and potassium hydroxide(227.3 g, 4.1 mol) in ethanol (500 mL) and water (500 mL) was refluxedfor 24 h. The reaction mixture was placed in an ice bath andhydrochloric acid (6N, 442 mL) was added. The ethanol was removed invacuo and the aqueous residue was extracted with diethyl ether. Theextracts were dried (MgSO₄) and concentrated in vacuo to give 309.3 g(100%) of 2-(2-(2-fluorophenyl)ethyl)malonic acid as an off-white solid.This product was used without further purification. NMR (DMSO-d₆): d6.8-6.2 (m, 4H, ArH), 2.4 (t, 1H, CH), 1.9 (q, 2H, CH₂), 1.3 (t, 2H,CH₂). IR (KB_(r)) 1691 CM⁻¹.

d) Preparation of4-(2-Fluorophenyl)butyric acid

The 2-(2-(2-fluorophenyl)ethyl)malonic acid (147 g, 0.65 mol) was heatedin an oil bath at 170° C. for 2.5 h. On cooling,4-(2-fluorophenyl)butyric acid (117.3 g, 99%) crystallized as a tansolid. This product was used without further purification. NMR (CDCl₃):d 7.6-7.0 (m, 4H, ArH), 3.0-1.8 (m, 6H, 3X CH₂). IR (neat) 1709 cm⁻¹.

e) Preparation of 5-Fluorotetralone

A mixture of 4-(2-fluorophenyl)butyric acid (100 g, 0.55 mol) andthionyl chloride (418.8 g, 3.51 mol) was refluxed for 3 h. The excessthionyl chloride was removed in vacuo to give 110.1 g (100%) of4-(2-fluorophenyl)butyryl chloride.

To the 4-(2-fluorophenyl)butyryl chloride in carbon disulfide (1.0 L) at-78° C. was added aluminum chloride (93.2 g, 0.7 mol) portionwise over a30 min period. The mixture was warmed to room temperature for 30 min,then refluxed for 2 h. The reaction mixture was poured into a mixture ofice (500 mL) and HCl (6N, 500 mL). The carbon disulfide layer wasseparated, washed with saturated sodium bicarbonate and extracted withethyl acetate. The aqueous phase was extracted with ethyl acetate. Thecombined extracts were dried (MgSO₄) and concentrated in vacuo to give84.2 g (93%) of 5-fluorotetralone as a tan solid. NMR (CDCl₃): d 7.7 (m,1H, ArH), 7.1 (m, 2H, ArH), 2.9 (t, 2H, CH₂), 2.6 (t, 2H, CH₂), 2.1 (q,2H, CH₂).

f) Preparation of(E)-N-Cyclopropyl-2-(5-fluoro-1,2,3,4-tetrahydro-1-naphthylidene)acetamide

To a stirred suspension of NaH (60% dispersion in mineral oil, Aldrich)in dimethyl sulfoxide at room temperature under N₂ was added diethyl(cyclopropyl carbamoylmethyl)phosphonate (21.5 g, 0.09 mol). Thereaction was slightly exothermic. To the resulting solution was added5-fluoro-1-tetralone (13.7 g, 0.08 mol) in dimethyl sulfoxide. Thereaction was stirred overnight at room temperature. The reaction waspoured into ice-cold water (800 ml) and extracted with four 500 mlportions dichloromethane. The organic phase was washed with eight 500 mlportions of water, filtered and spin evaporated in vacuo.

Chromatography on Silica gel using 35% to 50% ethyl acetate:hexanes aseluent followed by trituration of the resulting solid with pentane atroom temperature gave 5.07 g (25%) of(E)-N-cyclopropyl-2-(5-fluoro-1,2,3,4-tetrahydro-1-naphthylidene)acetamide,m.p., 148°-149° C.;

EXAMPLE 13 Preparation of(E)-N-Cyclopropyl-2-(7-fluoro-1,2,3,4-tetrahydro-1-naphthylidene)acetamide

a) Preparation of 3-(4-fluorobenzoyl)propionic acid

A mixture of fluorobenzene (104.4 g, 1.09 mol, Aldrich) and succinicanhydride (93.5 g, 0.93 mol) in 1,2-dichlorobenzene (530 mL) was heatedto 50° C. Aluminum chloride (245 g, 1.84 mol) was added portionwisekeeping the temperature below 60° C. After 4 h at 60° C. followed by 5 hat 80° C., the reaction mixture was poured into a mixture ofconcentrated HCl (200 mL) and ice water (2 L). The organic layer wasseparated and the aqueous phase was extracted with dichloromethane. Thecombined organic phase was dried and concentrated in vacuo. The residuewas poured into hexane (2 L) and the resulting solid was filtered andwashed with pentane to give 164.1 g (89%) of 3-(4-fluorobenzoyl)propionic acid as a white solid. m.p., 102°-104.5° C. (lit J. Org. Chem.26, 2667, 1961; m.p., 102.5°-103.5° C.);

b) Preparation of 4-(4-fluorophenyl)butyric acid

A mixture of 3-(4-fluorobenzoyl)propanoic acid (42.3 g, 0.22 mol) and10% Palladium on carbon (3 g) in acetic acid (250 mL) was hydrogenatedat 50 psi and 25° C. for 6 h. The mixture was filtered and concentratedin vacuo. The residue was distilled at 0.02 mm Hg and the productcrystallized to give 4-(4-fluorophenyl)butyric acid as a white solid(97%). m.p., 44°-46.2° C. (lit. J. Am. Chem. Soc. 89, 386, 1967; m.p.,45.5°-46.5° C.).

c) Preparation of 7-Fluoro-1-tetralone

A mixture of 4-(4-fluorophenyl)butyric acid (68.2 g, 0.37 mol) andthionyl chloride (155 g, 1.3 mol) was refluxed for 1.25 h. The mixturewas concentrated in vacuo to give 75.3 g (100%) of4-(4-fluorophenyl)butyryl chloride)

To a mixture of aluminum chloride (66 g, 0.50 mol) in carbon disulfide(600 mL) was added dropwise a solution of 4-(4-fluorophenyl)butyrylchloride (75.3 g, 0.37 mole) in carbon disulfide (260 mL) keeping theinternal temperature below 10° C. After refluxing for 0.5 h, thereaction mixture was poured into a mixture of concentrated HCl (50 mL)and ice water (800 mL). The mixture was filtered and extracted withdiethyl ether. The diethyl ether extracts were dried and concentratedit7 vacuo to give crude 7-fluoro-1-tetralone. Vacuum distillation gavepure 7-fluoro-1-tetralone b.p., 83° C. at 0.3 mm Hg which solidified toa white solid (94%). m.p., 62°-64° C. (lit, J. Am. Chem. Soc., 89, 386,1967, m.p., 63.5°-65.0° C.);

d) Preparation of(E)-N-Cyclopropyl-2-(7-fluoro-1,2,3,4-tetrahydro-1-naphthylidene)acetamide

This compound was prepared in an analogous manner to Example 12f withthe replacement of 5-fluoro1-tetralone and diethyl(cyclopropylcarbamoyl)methyl phosphonate with 7-fluoro-1-tetralone (7.76g, 0.05 mol) and diethyl(cyclo propylcarbamoyl)methylphosphonate (11.1g, 0.05 mol). Chromatography on Silica gel using ethyl acetate:hexanes(1:2) as eluent gave 4.38 g (37%) of(E)-N-Cyclopropyl-2-(7-fluoro-1,2,3,4-tetrahydro-1-naphthylidene)acetamide, m.p., 122.8°-123.3° C.; NMR (DMSO-d₆): d 8.00 (d, J=4.0Hz,1H), 7.32 (dd, J=11.2 Hz,1H), 7.04-7.23 (m, 2H), 6.33 (s, 1H), 3.06(m,2H), 2.69 (m, 3H), 1.70 (m, 2H), 0.66 (m, 2H), 0.40 (m, 2H);steady-state nOe: irradiation at 6.39 d, observed significant nOe at7.32 d.

Anal. Calcd. for C₁₅ H₁₆ FNO (mw 245.30): C, 73.45; H, 6.57; N, 5.71.Found: C, 73.38; H, 6.64; N, 5.67.

EXAMPLE 14 Preparation of(E)-2-(7-Fluoro-1,2,3,4-tetrahydro-1-naphthylidene)-N,N-dimethylacetamide

a) Preparation of Ethyl2-(7-Fluoro-1,2,3,4-tetrahydro-1-hydroxy-1-naphthyl)acetate

Ethyl acetate (5.4 g, 61 mmol) was added dropwise to a stirred, chilled(dry ice-acetone bath) solution of 1M lithium bis(trimethylsilyl)amidein tetrahydrofuran (61 mL, 0.061 mol, Aldrich) under nitrogen. After 15min, a solution of 7-fluoro-1-tetralone (10.0 g, 61 mmol) intetrahydrofuran (25 mL) was added dropwise and the resulting mixture wasstirred for 1 h (dry ice-acetone bath). A 1N solution of hydrochloricacid (61 mL) was added and the mixture was allowed to warm to roomtemperature. The organic phase was separated, dried over anhydroussodium sulfate, filtered and concentrated to a pale yellow oil (15.0 g,100%). An analytical sample was obtained by chromatographing a 1.5 gportion on Silica Gel 60 using dichloromethane-hexanes (1:1) as eluent.The fractions containing only ethyl2-(7-fluoro-1,2,3,4-tetrahydro-1-hydroxy-1-naphthyl)acetate werecombined and concentrated iii vacuo to give 1.2 g (80%) of a colorlessoil; NMR (DMSO-d₆): d 6.93-7.31 (m, 3H, Ar), 5.28 (s, 1H, OH), 3.98 (m,2H, CH₂ OOC), 2.60-2.87 (m, 4H, CH₂ CO, CH₂), 2.12-2.28 (m, 1H, CH),1.78-1.86 (m, 3H, CH, CH₂), 1.09 (t, 3H, CH₃).

b) Preparation of Ethyl2-(7-Fluoro-1,2,3,4-tetrahydro-1-naphthyl)acetate

Trifluoroacetic acid (20 mL) was added to a stirred, chilled(ice-methanol bath) solution of crude ethyl2-(7-fluoro-1,2,3,4-tetrahydro-1-hydroxy-1-naphthyl)acetate (10.0 g,35.8 mmol) in dichloromethane (180 mL). After 4 h, the mixture wasconcentrated in vacuo to a clear oil (8.3 g, 100%); NMR (DMSO-d₆): d6.94-7.65 (m, 3H, Ar), 6.45 (br s, 0.2 H, ═CH/E), 6.10 (t, 0.8H,═CH/endo), 4.08 (m, 2H, CH₂ OOC), 3.67, 3.51 (s's, 2.2H, H₂ O, CH₂/endo), 3.08, 2.70, 2.25, 1.77 (m's, 4.4H, 5×CH₂), 1.26 (t, 0.6H, CH₃/E), 1.17 (t, 2.4H, CH₃ /endo).

A portion of the above mixture of E and endo esters (2.3 g, 10 mmol),sodium hypophosphite hydrate (1.8 g, 20 mmol, Aldrich) and 10% palladiumon carbon (0.2 g) in 75% aq ethanol (20 mL) was heated to reflux for 2h. The mixture was filtered through celite and the filtrate wasconcentrated in vacuo. The residue in dichloromethane was washedsuccessively with water (100 mL) and brine (50 mL), dried over anhydroussodium sulfate, filtered, concentrated in vacuo and chromatographed onSilica Gel 60 using ethyl acetate-hexane (3:97) as eluent. The fractionscontaining only ethyl 2-(?-fluoro-1,2,3,4-tetrahydro-1-naphthyl)acetatewere combined and concentrated in vacuo to give 1.9 g (78%) of a paleyellow oil; NMR (DMSO-d₆): d 6.89-7.14 (m, 3H, Ar), 4.11 (q, 2H, CH₂OOC), 3.15-3.27 (m, 1H, CH), 2.44-2.82 (m, 4H, 2×CH₂), 1.52-1.90 (m, 4H,2×CH₂), 1.20 (t, 3H, CH₃).

c) Preparation of Ethyl2-Bromo-2-(7-fluoro-1,2,3,4-tetrahydro-1-naphthyl)acetate

To a stirred, chilled (dry ice-acetone bath) solution ofdiisopropylamine (0.3 mL, 1.9 mmol, Aldrich) in tetrahydrofuran (3 mL)under nitrogen was successively added 2.5N n-butyl lithium in hexane(0.8 mL, Aldrich), chlorotrimethylsilane (0.2 mL, 1.8 mmol, Aldrich) andethyl 2-(7-fluoro-1,2,3,4-tetrahydro-1-naphthyl)acetate (236 mg, 1.0mmol). The resulting clear solution was stirred for 1 h, treated withN-bromosuccinimide (180 mg, 1.0 mmol, Aldrich) and stirred for anadditional 0.5 h before the dry ice-acetone bath was removed. Thereddish cloudy solution was stirred for 2 h at room temperature, treatedwith dilute aq hydrochloric acid (4 meq) and extracted with diethylether (30 mL). The ether layer was dried over anhydrous sodium sulfate,filtered, concentrated in vacuo and chromatographed on Silica Gel 60using dichloromethane-hexane (1:9) as eluent. Fractions containing onlyethyl 2-bromo-2-(7-fluoro-1,2,3,4-tetrahydro-1-naphthyl)acetate as a 1:4isomeric mixture were combined and concentrated in vacuo to a clear oil(171mg, 54%); NMR (DMSO-d₆): d 7.00-7.18 (m, 3H, Ar), 5.20 (d, J=6.2 Hz,0.8H, BrCHCO), 5.17 (d, J=6.2 Hz, 0.2H, BrCHCO), 4.19 (q, 1.6H, CH₂OOC), 4.14 (q, 0.4H, CH₂ OOC), 3.49 (m, 1H, ArCH), 2.69 (m, 2H, ArCH₂),1.81-1.97 (m, 3H, CH, CH₂), 1.61-1.67 (m, 1H, CH), 1.21 (t, 2.4H, CH₃),1.07 (t, 0.6H, CH₃).

d) Preparation of(E)-2-(7-Fluoro-1,2,3,4-tetrahydro-1-naphthylidene)acetic Acid

A mixture of ethyl2-bromo-2-(7-fluoro-1,2,3,4-tetrahydro-1-naphthyl)acetate (2.2 g, 7.0mmol), 1N potassium tert-butoxide in tetrahydrofuran (14 mL, Aldrich)and tert-butanol (140 mL) was stirred for 5 h at room temperature. Theresulting suspension was concentrated in vacuo, diluted with water (200mL) and washed with diethyl ether. The aqueous layer was acidified byadding 1N hydrochloric acid (14 mL) and extracted with diethyl ether.The ether extract was dried over anhydrous sodium sulfate, filtered,concentrated in vacuo and chromatographed on Silica Gel 60 using ethylacetate-hexane (1:1) as eluent. The fractions containing only(E)-2-(7-fluoro-1,2,3,4-tetrahydro-1-naphthylidene)acetic acid werecombined and concentrated in vacuo to give a white solid (0.8 g, 55%);NMR (DMSO-d₆): d 12.22 (br s, 1H, COOH), 7.57 (d of d, J_(m) =2.6 Hz,J_(o) =11.0 Hz, 1H, Ar), 7.12-7.28 (m, 2H, Ar). 6.36 (s, 1H, ═CH, E),3.04 (t, 2H, ArCH₂), 2.74 (t, 2H, CH₂), 1.74 (m, 2H, CH₂); steady-statenOe: irradiation at 6.36, observed 25% nOe at 7.57.

e) Preparation of(E)-2-(7-fluoro-1,2,3,4-tetrahydro-1-naphthylidene)acetyl chloride

Oxalyl chloride (3 ml, 0.034 mol, Aldrich) was added to a suspension of(E)-2-(7-fluoro-1,2,3,4-tetrahydro-1-naphthylidene)acetic acid (2.03 g,0.01 mol) in toluene (35 ml) at 0° C. while protected from moisture by anitrogen atmosphere. The stirring mixture was allowed to warm to 25° C.and was stirred for 1.5 h. Concentration in vacuo gave(E)-2-(7-fluoro-1,2,3,4-tetrahydro-1-naphthylidene)acetyl chloride whichwas dissolved in dichloromethane and used without purification.

f) Preparation of(E)-2-(7-fluoro-1,2,3,4-tetrahydro-1-naphthylidene)-N,N-dimethylacetamide

Dimethylamine (3 ml, 0.045 mol, Kodak) was added to a chilled (ice bath)solution of (E)-2-(7-fluoro-1,2,3,4-tetrahydro-1-naphthylidene)acetylchloride (2.3 g, 0.010 mol) in dichloromethane (35 ml). The reaction waswarmed to 25° C. and stirred for 1.5 h. The volatiles were removed byspin evaporation in vacuo to give a beige residue. This residue wasdissolved in ethyl acetate (200 ml), washed with deionized water (50ml), and the organic layer was concentrated by spin evaporation invacuo. The residue was chromatographed on Silica Gel 60 using a stepgradient from ethyl acetate-hexanes/1:5 to ethyl acetate. Fractionscontaining(E)-2-(7-fluoro-1,2,3,4-tetrahydro-1-naphthylidene)-N,N-dimethylacetamidewere combined and concentrated by spin evaporation in vacuo to a whitesolid. Recrystallization from dichloromethane-hexanes gave 1.62 g (70%)of(E)-2-(7-fluoro-1,2,3,4-tetrahydro-1-naphthylidene)-N,N-dimethylacetamideas a white crystalline solid; m.p., 66°-70° C.

Anal.Calcd. for C₁₄ H₁₆ FNO (mw 233.278); C, 72.08; H,691; N,6.00.Found: C,71.97; H,6.94; N,5.95.

EXAMPLE 15 Preparation of(E)-2-(6-Fluoro-3,3-dimethyl-1-indanylidene)acetamide

a) Preparation of Diethyl Isopropylidenemalonate

Diethyl isopropylidenemalonate was prepared according to the procedureof E. L. Eliel, R. O. Hutchins, and Sr. M. Knoeber, Organic SynthesisColl. Vol. VI, 442, 1988, with following modifications. A mixture ofacetone (54 g, 0.93 mol, Mallinckrodt), diethyl malonate (100 g, 0.62mol, Aldrich), acetic anhydride (80 g, 0.78 mol, Mallinckrodt), and zincchloride (12.5 g, 0.78 mol, Aldrich) was refluxed (90° C. oil bath) for18 h while protected from moisture. The reaction solution was dilutedwith dichloromethane (500 ml) and washed with cold water (3×50 ml). Theaqueous washes were combined and extracted with dichloromethane. Alldichloromethane layers were combined and concentrated by spinevaporation in vacuo. The residual oil was distilled under vacuum andthe fractions boiling at 102°-138° C. at 12 Torr were combined with thepot residue and heated for 6 h with a 200° C. oil bath. The dark oil wasredistilled to give 40.1 g (32%) of diethyl isopropylidenemalonate as aclear oil: b.p., 110°-115° C./12 mmHg;

b) Preparation of Diethyl 2-(2-(4-Fluorophenyl)-2-methylethyl)malonate

A mixture of 4-fluorophenylmagnesium bromide (82 ml of a 2N solution inethyl ether, 0.164 mol, Aldrich) and copper(I) iodide (0.310 mg, 1.63mmol, Aldrich) was stirred for 15 min at -10° C. while blanketed with anitrogen atmosphere. To this mixture was added a solution of diethylisopropylidenemalonate (29.6 g, 0.148 mol) in anhydrous diethyl ether(250 ml) in a thin stream with rapid stirring. The resulting solutionwas stirred at -10° C. for 2 h, at 25° C. for 30 min and then pouredwith rapid stirring into 0.5 kg of crushed ice containing 30 ml of 12Nhydrochloric acid. The layers were separated and the aqueous layer wasextracted with ethyl ether (3×400 ml). All ether layers were combinedand washed with deionized water (2×25 ml), saturated aqueous sodiumbicarbonate (25 ml), and deionized water (25 ml). The etheral layer wasconcentrated by spin evaporation in vacuo and the residue was distilledto give 25.9 g (59%) of diethyl2-(2-(4-fluorophenyl)-2-methylethyl)malonate as a clear oil (b.p.,140°-145° C./0.01 mmHg);

c) Preparation of 3-(4-Fluorophenyl)-3-methylbutyric Acid

A solution of diethyl 2-(2-(4-fluorophenyl)-2-methylethyl)malonate (41g, 0.138 mol) and potassium hydroxide 85% (18.25 g, 0.277 mol,Mallinkrodt) in 250 ml of deionized water was vigorously refluxed for 4hours with an 150° C. oil bath. After cooling with an ice bath, thesolution was neutralized with 18N sulfuric acid (23 ml, 0.414 mol,Mallinkrodt), and extracted with dichloromethane (4×250 ml). Thedichloromethane extracts were combined, washed with water, andconcentrated by spin evaporation in vacuo. The residue was slurried withwater and the crystalline product was collected by filtration to give24.3 g (90%) of 3-(4-fluorophenyl)-3-methylbutyric acid, m.p., 45°-57°C.;

d) Preparation of 3-(4-Fluorophenyl)-3-methylbutyryl Chloride

Oxalyl chloride (46.5 g, 0.367 mol, Aldrich) was added to a solution of3-(4-fluorophenyl)-3-methylbutyric acid (24 g, 0.122 mol) at -10° C.while protected from moisture by a nitrogen atmosphere. The stirringmixture was allowed to warm to 25° C. and was stirred for 2 h.Fractional distillation gave 26.6 g (76%) of3-(4-fluorophenyl)-3-methylbutyryl chloride as a clear oil, b.p.,132°-138° C.;

e) Preparation of 6-Fluoro-3,3-dimethyl-1-indanone

A solution of 3-(4-fluorophenyl)-3-methylbutyryl chloride (19.0 g,0.0815 mol) in dichloromethane (100 ml) was added dropwise over 2.5 h toa stirring mixture of aluminum chloride (13.57 g, 0.102 mol, Aldrich) indichloromethane (200 ml) while protected from moisture by a nitrogenatmosphere. After stirring 18 h at 25° C., the reaction solution waspoured over ice (400 g) and the resulting solution was extracted withdichloromethane (2×200 ml). The dichloromethane layers were combined,washed with deionized water (50 ml), and concentrated by spinevaporation in vacuo. The residue was dissolved in ethyl acetate andwashed through a pad of silica gel. The pad was washed with additionalethyl acetate. Removal of the volatiles from the combined washes by spinevaporation in vacuo gave 15.2 g (99%) of6-fluoro-3,3-dimethyl-1-indanone as a light yellow oil whichcrystallized on standing, m.p., 57°-62° C.;

f) Preparation of Ethyl2-(6-Fluoro-1-hydroxy-3,3-dimethyl-1-indanyl)acetate

This compound was prepared in a similar manner to ethyl2-(6-fluoro-1-hydroxy-1-indanyl)acetate in Example 1d by substituting6-fluoro-3,3-dimethyl-1-indanone for 6-fluoro-1-indanone and preparingthe activated zinc by heating zinc dust (Aldrich) with iodine (Aldrich)without solvent. Removal of the volatiles from the workup solution byspin evaporation in vacuo gave 16.2 g (82%) of ethyl2-(6-fluoro-1-hydroxy-3,3-dimethyl-1-indanyl)acetate as a light yellowoil;

g) Preparation of (E)-2-(6-Fluoro-3,3-dimethyl-1-indanylidene)aceticAcid

A solution of ethyl 2-(6-fluoro-1-hydroxy-3,3-dimethyl-1-indanyl)acetate(16 g, 0.0601 mol) in 1N sodium hydroxide (60.1 ml, 0.0601 mol) andethanol (60 ml) was stirred for 20 h. The solution was concentrated to asmall volume by spin evaporation in vacuo, diluted with deionized water(100 ml), and acidified to pH 3 with 1N hydrochloric acid This biphasicsolution was extracted with dichloromethane (2×100 ml). The extractswere combined, washed with deionized water (20 ml), dried with magnesiumsulfate (Mallinckrodt), and concentrated by spin evaporation in vacuo.The residue was dissolved in dichloromethane (30 ml), cooled to 0° C.,and diluted with 400 ml of a cold (0° C.) solution of trifluoroaceticacid (45 g, Aldrich) in dichloromethane (400 ml). After 15 min. thesolution was concentrated by spin evaporation in vacuo and the residuewas crystallized by adding hexanes to give 9.23 g (70%) of(E)-2-(6-fluoro-3,3-dimethyl-1-indanylidene)acetic acid as a whitecrystalline solid, m.p., 202°-203.5° C.;

h) Preparation of (E)-2-(6-Fluoro-3,3-dimethyl-1-indanylidene)acetylChloride

To an ice cold, stirred suspension of(E)-2-(6-fluoro-3,3-dimethyl-1-indanylidene)acetic acid (9.0 g, 0.0409mol) in dichloromethane (200 ml) was added oxalyl chloride (15.6 g,0.123 mol, Aldrich). The stirring suspension was allowed to warm to 25°C. during 2 h. The resulting solution was concentrated by spinevaporation in vacuo with the addition of dichloromethane (4×75 ml) togive (E)-2-(6-fluoro-3,3-dimethyl-1-indanylidene)acetyl chloride as anuncharacterized oil. Dichloromethane (approximately 70 g) was added todissolve this residual oil and the resulting solution was dividedequally and used without other purification in Examples 15i, 16 and 17.

i) Preparation of (E)-2-(6-Fluoro-3,3-dimethyl-1-indanylidene)acetamide

A solution of 30% aqueous ammonium hydroxide (10 ml, 76 mmol,Mallinckrodt) was added to the solution of(E)-2-(6-fluoro-3,3-dimethyl-1-indanylidene)acetyl chloride (0.01363mol) obtained from Example 41h diluted with dichloromethane (200 ml) andcooled to 0° C. The biphasic solution was stirred rapidly and allowed towarm to room temperature over 18 h. The reaction solution wasconcentrated by spin evaporation in vacuo, diluted with dichloromethane(200 ml), and washed with IN aqueous hydrochloric acid (McIntosh), asolution of 5% aqueous sodium bicarbonate (Mallinckrodt), dried withmagnesium sulfate (Mallinckrodt), and concentrated by spin evaporationin vacuo. The residue was chromatographed on Silica Gel 60 using ethylacetate-hexanes (1:1), and then ethyl acetate. Fractions containing(E)-2-(6-fluoro-3,3-dimethyl-1-indanylidene) acetamide were combined andconcentrated by spin evaporation in vacuo. Recrystallization fromdichloromethane-hexanes gave 2.85 g (95%) of(E)-2-(6fluoro-3,3-dimethyl-1-indanylidene)acetamide as a whitecrystalline solid, m.p., 167°-168° C.;

EXAMPLE 16 Preparation of(E)-2-(6-Fluoro-3,3-dimethyl-1-indanylidene)-N-methylacetamide

This compound was prepared in an analogous manner to Example 15i withthe replacement of the solution of 30% aqueous ammonium hydroxide with a40% aqueous solution of methylamine (10 ml, Aldrich). Recrystallizationfrom dichloromethane-hexanes gave 2.89 g (91%) of(E)-2-(6-fluoro-3,3-dimethyl-1-indanylidene)-N-methylacetamide as awhite crystalline solid, m.p., 157°-158° C.;

EXAMPLE 17 Preparation of(E)-N-Cyclopropyl-2-(6-fluoro-3,3-dimethyl-1-indanylidene)acetamide

This compound was prepared in an analogous manner to Example 15i withthe replacement of the solution of 30% aqueous ammonium hydroxide withcyclopropyl amine (4 ml, Aldrich). Recrystallization fromdichloromethane-hexanes gave 2.86 g (81%) of(E)-N-cyclopropyl-2-(6-fluoro-3,3-dimethyl-1-indanylidene)acetamide as awhite crystalline solid, m.p., 149°-150° C.;

EXAMPLE 18 Preparation of(E)-2-(6-Fluoro-3-methyl-1-indanylidene)acetamide

a) Preparation of Ethyl 4-Fluorocinnamate

A solution of butyl lithium, 2.5M in hexanes (159 ml, 0.3975 mol,Aldrich), was added dropwise over 0.25 hr, with rapid mechanicalstirring, to a solution of triethyl phosphonoacetate (89.2 g, 0.389 mol,Aldrich) in tetrahydrofuran (800 ml, anhydrous, Aldrich) at <5° C. whileblanketed with a nitrogen atmosphere. This solution was stirred for anadditional 0.25 hr and cooled to 0° C. with an ice bath and a solutionof 4'-fluoroacetophenone (50 g, 0.362 mol, Aldrich) in tetrahydrofuran(50 ml) was then added in one portion. Stirring was continued for 18 hrwithout additional cooling. The solution was then concentrated to ˜100ml by spin evaporation in vacuo and diluted to 500 ml with ethylacetate. After washing with deionized water (3×50 ml) this solution wasconcentrated by spin evaporation in vacuo. Distillation at reducedpressure gave 48 g (63%) of ethyl 4-fluorocinnamate as a mixture of (E)to (Z) isomers (ratio 3:1) contaminated with 16% of triethylphosphonacetate as a clear oil, b.p., 138- 143° C. at 14 Torr;

b) Preparation of Ethyl 3-(4-Fluorophenyl)butyrate

A mixture of ethyl 4-fluorocinnamate (47.5 g, 0.228 mol) and 10%palladium on carbon (0.85 g, Aldrich) in 95% ethanol was shaken in aParr hydrogenator under 2-3 atm of H₂ pressure for 1 h. The mixture wasfiltered and concentrated by spin evaporation in vacuo. Fractionaldistillation gave 46.5 g (97%) of ethyl 3-(4-fluorophenyl)butyrate as aclear oil, b.p., 122°-128° C.: c) Preparation of3-(4-Fluorophenyl)butanoic Acid.

c) Preparation of 3-(4-Fluorophenyl)butanoic Acid

A solution of ethyl 3-(4-fluorophenyl)butyrate (45.3 g, 0.215 mol), 85%potassium hydroxide (14.22 g, 0.215 mol, Mallinckrodt) in 200 ml ofdeionized water was refluxed for 2 h, concentrated by spin evaporationin vacuo, made acidic (pH 3) with 12N hydrochloric acid (Mallinckrodt),and extracted with dichloromethane (4×200 ml). The dichloromethanelayers were combined, washed with deionized water (50 ml), andconcentrated by spin evaporation in vacuo. The residue was crystallizedfrom dichloromethane-hexanes to give 34.5 g (88%) of3-(4-fluorophenyl)butyric acid as a white crystalline solid;

d) Preparation of 3-(4-Fluorophenyl)butyryl Chloride

Oxalyl chloride (71 g, 48.8 ml, 0.560 mol, Aldrich) was added to amixture of 3-(4-fluorophenyl)butyric acid (34 g, 0.187 mol) in 200 ml ofdichloromethane at -5° C. After stirring for 20 min at this temperature,the solution was allowed to warm to 25° C. and stirring was continuedfor 2 h. The volatiles were removed by spin evaporation in vacuo withthe addition of dichloromethane (4 ×) during concentration to give 35.1g (94%) of 3-(4-fluorophenyl)butyryl chloride as a light yellow oil;

e) Preparation of 6-Fluoro-3-methyl-1-indanone

This compound was prepared in an analogous manner to Example 15e withthe replacement of 3-(4-fluorophenyl)-3-methyl-butyryl chloride with3-(4-fluorophenyl)butyryl chloride (35.1 g, 174.9 mmol). Removal of thevolatiles from the combined washes by spin evaporation in vacuo gave26.3 g (92%) of 6-fluoro-3-methyl-1-indanone as an oil which formed lowmelting crystals on standing;

f) Preparation of Ethyl 2-(6-Fluoro-1-hydroxy-3-methyl-1-indanyl)acetate

This compound was prepared in an analogous manner to Example 15f withthe replacement of 6-fluoro-3,3-dimethyl- I -indanone with6-fluoro-3-methyl-1-indanone (25 g. 140 mmol). Removal of the volatilesfrom the workup solution gave 15.0 g (45%) of ethyl2-(6-fluoro-1-hydroxy-3-methyl-1-indanyl)acetate as a light tan oil;

g) Preparation of (E)-2-(6-Fluoro-3-methyl-1-indanylidene)acetic Acid

This compound was prepared in an analogous manner to Example 15g withthe replacement of ethyl2-(6-fluoro-1-hydroxy-3,3-dimethyl-1-indanyl)acetate with ethyl2-(6-fluoro-1-hydroxy-3-methyl-1-indanyl)acetate (15 g, 59.5 mmol).Removal of the volatiles from workup gave 9.3 g (76%) of(E)-2-(6-fluoro-3-methyl-1-indanylidene)acetic acid as a tan solid,m.p., 175°-177° C.;

h) Preparation of (E)-2-(6-Fluoro-3-methyl-1-indanylidene)acetylChloride

This compound was prepared in an analogous manner to Example 15h withthe replacement of (E)-2-(6-fluoro-3,3-dimethyl-1-indanylidene)aceticacid with (E)-2-(6-fluoro-3-methyl-1-indanylidene)acetic acid (9 g, 43.6mmol). The product residue was dissolved in dichloromethane and used,without purification, in Example 17, 18, and 19.

i) Preparation of (E)-2-(6-Fluoro-3-methyl-1-indanylidene)acetamide

This compound was prepared in an analogous manner to Example 15i withthe replacement of (E)-2-(6-fluoro-3,3-dimethyl-1-indanylidene)acetylchloride with (E)-2-(6-fluoro-3-methyl-1-indanylidene)acetyl chloride(3.26 g, 14.5 mmol). Recrystallization from dichloro- methanehexanesgave 2.39 g (77%) of (E)-2-(6-fluoro-3-methyl-1-indanylidene)acetamideas a white crystalline solid, m.p., 149°-151° C.;

EXAMPLE 19 Preparation of(E)-2-(6-Fluoro-3-methyl-1-indanylidene)-N-methylacetamide

This compound was prepared in an analogous manner to Example 16 with thereplacement of (E)-2-(6-fluoro-3,3-dimethyl-1-indanylidene)acetylchloride with (E)-2-(6-fluoro-3-methyl-1-indanylidene)acetyl chloride(3.26 g, 14.5 mmol). Recrystallization from dichloro- methanehexanesgave 2.27 g (71%) of(E)-2-(6-fluoro-3-methyl-1-indanylidene)N-methylacetamide as a whitecrystalline solid, m.p., 168°-169° C.;

EXAMPLE 20 Preparation of(E)-N-Cyclopropyl-2-(6-fluoro-3-methyl-1-indanylidene)acetamide

This compound was prepared in an analogous manner to Example 17 with thereplacement of (E)-2-(6-fluoro-3,3-dimethyl-1-indanylidene)acetylchloride with (E)-2-(6-fluoro-3-methyl-1-indanylidene)acetyl chloride(3.26 g, 14.5 mmol). Recrystallization from dichloromethane-hexanes gave2.30 g (67%) of(E)-N-cyclopropyl-2-(6-fluoro-3-methyl-1-indanylidene)acetamide as awhite crystalline solid. m.p., 132°-134° C.;

EXAMPLE 21 Preparation of(Z)-2-(6-fluoro-2-hydroxy-1-indanylidene)acetamide (Method A)

a) Preparation of (Z)-2-(2-bromo-6-fluoro-1-indanylidene)acetamide

N-Bromosuccinimide (22.57 g, 126.8 mmoles, Aldrich) and benzoyl peroxide(1.89 g, 7.8 mmoles, Aldrich) were added to a suspension of(E)-2-(6-fluoro-1-indanylidene)acetamide (21.00 g, 109.8 mmoles) incarbon tetrachloride (400 mL) and benzene (400 mL). The mixture wasrefluxed under a calcium chloride drying tube while shining an infraredlamp on it for two hours, after which time an orange solution formed.The heat and light were removed, and the solution was stirred at ambienttemperature for 18 hours. The mixture was filtered, and the solids werewashed with ethyl acetate. The washings and filtrate were combined andevaporated in vacuo. The residue was dissolved in ethyl acetate (800 mL)and washed with water (3×200 mL) and brine (200 mL), dried over sodiumsulfate, filtered and evaporated in vacuo. The residue waschromatographed on silica gel eluting first with hexane: ethyl acetate(2:1) gradually increasing the polarity to hexane: ethyl acetate (1:1).The fractions containing the major spot were combined and evaporated invacuo to give a yellow solid which was dried in a vacuum at 70° C. for18 hours to give 1.022 g (3%) of(Z)-2-(2-bromo-6-fluoro-1-indanylidene)acetamide as a yellow solid, mp162°-163° C. ¹ H-NMR

b) A mixture of (Z)-2-(2-bromo-6-fluoro-1-indanylidene)acetamide (5.30g, 19.25 mmoles) and silver nitrate (10.40 g, 61.18 mmoles, Aldrich) indimethoxyethane (265 mL) and water (100 mL) was refluxed for 18 hours.The mixture was filtered, and the filtrate was diluted with water (700mL) and extracted with ethyl acetate (6×100 mL). The combined extractswere washed with water (200 mL) and brine (200 mL), dried over magnesiumsulfate, filtered, and evaporated in vacuo. The residue waschromatographed on silica gel, eluting with hexane: ethyl acetate (2:1),gradually increasing the polarity to hexane: ethyl acetate (1:1). Thefractions containing the compound with Rf=0.18 were combined andevaporated in vacuo to give 1.13 g (28%) of crude(Z)-2-(6-fluoro-2-hydroxy-1-indanylidene)acetamide as an orange solid.Recrystallization from ethyl acetate: hexane mixtures gave 0.49 g (12%)of (Z)-2-(6-fluoro-2-hydroxy-1-indanylidene)acetamide as an off-whitesolid, mp 201°-202° C.;

c) Preparation of (Z)-2-(6-fluoro-2-hydroxy-1-indanylidene)acetamide(Method B)

A suspension of (E)-2-(6fluoro-1-indanylidene)acetamide (12.00 g, 62.8mmoles) in dichloromethane (250 mL) was added to a solution of seleniumdioxide (5.20 g, 46.9 mmoles, Aldrich) and tert-butyl hydroperoxide (25mL, 260.8 mmoles, Aldrich) in dichloromethane (500 mL). The suspensionwas stirred at ambient temperature for 3 days. Additional tert-butylhydroperoxide (10 mL, 104.3 mmoles) was added, and the mixture wasstirred at ambient temperature for 18 hours. Additional selenium dioxide(5.00 g, 45.1 mmoles) was added, and the mixture was stirred at ambienttemperature for 18 hours. Additional tert-butyl hydroperoxide (15 mL,156.5 mmoles) was added, and the mixture was stirred at ambienttemperature for 18 hours. The mixture was filtered to remove about onegram of impure product, and the filtrate was dried over magnesiumsulfate, filtered, and evaporated in vacuo. Additional selenium dioxide(5.00 g, 45.1 mmoles) was added, and the mixture was stirred at ambienttemperature for 18 hours. The mixture was concentrated in vacuo to 300mL, hexane was added, and the precipitate was collected by filtration,washed with hexane, and combined with the solids collected previously.The combined solids were dissolved in ethyl acetate (700 mL), washedsuccessively with water (3×100 mL) and brine (100 mL), concentrated invacuo to 100 mL, and cooled in an ice bath. The solids were collected byfiltration, and the filtrate was concentrated in vacuo to give a secondcrop of solids. All of the solids were combined and chromatographed onsilica gel, eluting with hexane: ethyl acetate (1:1). The fractionscontaining the major spot were combined and evaporated in vacuo to give5.80 g of an off-white solid, which was washed with chloroform (3×50 mL)to give 5.43 g (42%) of(Z)-2-(6-fluoro-2-hydroxy-1-indanylidene)acetamide as a white solid; mp202°-204° C.;

EXAMPLE 22 (Z)-2-(4,6-Difluoro-2-hydroxy-1-indanylidene)acetamide

A suspension of (E)-2-(4,6-difluoro-1-indanylidene)acetamide (10.0 g,0.05 mol, prepared as in Example 5g in dichloromethane (250 mL) wasadded portionwise over a 10 min. period to a mixture of 70% aqueoust-butylhydroperoxide (19.8 mL, 0.15 mol, Aldrich) and selenium dioxide(3.7 g, 0.03 mol, Aldrich) in dichloromethane (500 mL) at ambienttemperature. After 18 h, additional t-butylhydroperoxide (10 mL of a5.0M solution in 2,2,4-trimethylpentane, 0.05 mol, Aldrich) and seleniumdioxide (1.8 g, 0.02 mol) were added and the mixture was stirred atambient temperature. After 18 h, additional t-butylhydroperoxide (10 mLof 70% aqueous solution, 0.08 mol) and selenium dioxide (3.7 g, 0.05mol) were added and the mixture was stirred at ambient temperature for 8days. The resulting solid was filtered off and washed withdichloromethane to give 5.85 g of crude(Z)-2-(4,6-difluoro-2-hydroxy-1-indanylidene)acetamide. After 7 days atambient temperature a second crop of crude(Z)-2-(4,6difluoro-2-hydroxy-1-indanylidene)acetamide was obtained fromthe filtrate. Column chromatography on silica gel using ethyl acetate asthe eluent followed by a second column chromatography on silica gelusing ethyl acetate:hexanes (3:2) as eluent and trituration of theresulting solid with pentane gave 2.38 g of(Z)-2-(4,6-difluoro2-hydroxy-1-indanylidene)acetamide as a pink solid:m.p. 235°-237° C.;

EXAMPLE 23 Preparation of(E)-2-(6-fluoro-3-hydroxy-1-indanylidene)acetamide

a) Preparation of 3-bromo-6-fluoro-1-indanone

A mixture of N-bromosuccinimide (2.76 g, 15.51 mmoles, Aldrich), benzoylperoxide (0.01 g, 0.04 mmoles, Aldrich) and 6fluoro-1-indanone (2.29 g,15.25 mmoles) in carbon tetrachloride (20 mL) was refluxed undernitrogen for two hours. The mixture was cooled to ambient temperature,filtered, and the solids were washed with dichloromethane. The washingsand filtrate were combined, washed successively with 1.0N sodiumhydroxide (2×30 mL), water (2×30 mL) and brine (30 mL), and evaporatedin vacuo. The residue was chromatographed on silica gel eluting firstwith hexane, gradually increasing the polarity to hexane: ethyl acetate(95:5). The fractions containing the major spot were combined andevaporated in vacuo to give a 2.30 g (66%) of3-bromo-6-fluoro-1-indanone as a yellow oil which was used withoutfurther purification.

b) Preparation of 3-hydroxy-6-fluoro-1-indanone

A mixture of 3-bromo-6-fluoro-1-indanone (2.50 g, 10.0 mmoles) andsilver carbonate (4.19 g, 15.2 mmoles, Aldrich) in dimethoxyethane (85mL) and water (65 mL) was stirred overnight at ambient temperature. Themixture was filtered through a pad of celite, and the filtrate wasdiluted with water (500 mL) and extracted with ethyl acetate (4×100 mL).The combined extracts were washed with water (100 mL) and brine (75 mL),dried over sodium sulfate, filtered, and evaporated in vacuo to give2.80 g (quantitative) of crude 3-hydroxy-6-fluoro-1-indanone which wasused without further purification. Chromatography of 0.41 g on silicagel, eluting with hexane: ethyl acetate (3:4) gave 0.050 g ofanalytically pure 3-hydroxy-6-fluoro-1-indanone as a tan solid, mp73°-76° C.;

c) Preparation of 3-((tert-butyldimethylsilyl)oxy)-6-fluoro-1-indanone

A solution of 3-hydroxy-6-fluoro-1-indanone (4.09 g, 24.6 mmoles) indimethylformamide (10 mL) was added to a solution oftert-butyldimethylsilyl chloride (4.60 g, 30.5 mmoles, Aldrich) andimidazole (4.22 g, 62.0 mmoles, Aldrich) in dimethylformamide (20 mL).The solution was stirred at ambient temperature for 18 hours andevaporated in vacuo. The residue was dissolved in dichloromethane (200mL) and washed with water (6×75 mL) and brine (100 mL), dried overmagnesium sulfate, filtered and evaporated in vacuo. The residue waschromatographed on silica gel eluting with hexane: ethyl acetate (95:5).The fractions containing the major spot were combined and evaporated invacuo, and the residue was dried in a vacuum at ambient temperature for18 hours to give 4.14 g (60%) of3-((tert-butyldimethylsilyl)oxy)-6-fluoro-1-indanone as a white solid,mp 56°-58° C.;

d) Preparation of Ethyl2-(3-((tert-butyldimethylsilyl)oxy)-6-fluoro-1-hydroxy-1-indanyl)acetate

A solution of ethyl acetate (1.00 mL, 10.3 mmoles) and lithiumdiisopropylamine This salt was prepared from diisopropylamine (1.41 mL,10.0 mmoles, Aldrich) and n-butyl lithium (4.00 mL of a 2.5M hexanesolution, 10.0 mmoles, Aldrich)!, in tetrahydrofuran (15 mL) was stirredat -78° C. under nitrogen for 15 minutes. A solution of3-((tert-butyldimethylsilyl)oxy)-6-fluoro-1-indanone (2.80 g, 10.0mmoles) in tetrahydrofuran (15 mL) was added dropwise over a 7 minuteperiod, and the solution was stirred at -78° C. under nitrogen for 1.5hours. A solution of ammonium chloride (1.60 g, 30.0 mmoles) in water (9mL) was added, and the resulting suspension was allowed to warm toambient temperature. The layers were separated, and the aqueous layerwas extracted with ether (2×100 mL). The organic extracts were combinedand washed successively with water (100 mL) and brine (100 mL), driedover magnesium sulfate, filtered and evaporated ii vacuo. The residuewas chromatographed on silica gel eluting with hexane: ethyl acetate(98:2), gradually increasing the polarity to hexane: ethyl acetate(4:1). The fractions containing the major spot were combined andevaporated in vacuo, and the residue was dried in a vacuum at ambienttemperature for 18 hours at 60° C. to give 2.86 g (78%) of ethyl2-(3-((tert-butyldimethylsilyl)oxy)-6-fluoro-1-hydroxy-1-indanyl)acetate as a clear oil;

e) Preparation of (E)-Ethyl2-(3-((tert-butyldimethylsilyl)oxy)-6-fluoro-1-indanylidene) acetate

A solution of ethyl2-(3-((tert-butyldimethylsilyl)oxy)-6-fluoro-1-hydroxy-1-indanyl)acetate (2.80 g, 7.6 mmoles) was added to a solution of bis2,2,2-trifluoro-1-phenyl-1-(trifluoromethyl)-ethoxy!diphenylsulfurane(6.30 g, 9.4 mmoles, Fluka) in dichloromethane (50 mL) under a nitrogenatmosphere. The solution was stirred at ambient temperature for 35minutes and poured into water (500 mL). The organic layer was separated,washed with brine (250 mL), dried over magnesium sulfate, filtered andevaporated in vacuo. The residue was chromatographed on silica geleluting with hexane: ethyl acetate (99:1). The fractions containing themajor spot (and also a minor impurity) were combined and evaporated invacuo to give 2.68 g (quantitative) of crude (E)-ethyl2-(3-((tert-butyldimethylsilyl)oxy)-6-fluoro-1-indanylidene) acetate asa yellow oil which was used without further purification;

f) Preparation of(E)-2-(3-((tert-butyldimethylsilyl)oxy)-6-fluoro-1-indanylideneacetamide

A solution of dimethylaluminum amide was prepared by adding trimethylaluminum (6.5 mL of a 2.0M toluene solution, 13.0 mmoles, Aldrich) to asolution of ammonium chloride (0.695 g, 13.0 mmoles) in dichloromethane(25 mL) under a nitrogen atmosphere and stirring for 45 minutes atambient temperature. This solution of dimethylaluminum amide (13.0mmoles) was added to a solution of (E)-ethyl2-(3-((tert-butyldimethylsilyl)oxy)-6-fluoro-1-indanylidene) acetate(1.190 g, 3.4 mmoles) in dichloromethane (60 mL) under a nitrogenatmosphere. The mixture was stirred at ambient temperature for 30minutes and refluxed for 18 hours. After cooling to ambient temperatureand then in an ice bath, the mixture was quenched by dropwise additionof 0.5N hydrochloric acid until gas evolution ceased. The solution wasdiluted with water (50 mL), the layers were separated, and the aqueouslayer was extracted with dichloromethane (75 mL). The organic layerswere combined, washed successively with water (75 mL) and brine (75 mL),dried over magnesium sulfate, filtered and evaporated in vacuo. Theresidue was recrystallized from dichloromethane: hexane mixtures to give0.321 g (29%) of(E)-2-(3-((tert-butyldimethylsilyl)oxy)-6fluoro-1-indanylidene)acetamide as a white solid, mp 160°-165° C.;

g) Preparation of (E)-2-(6-fluoro-3-hydroxy-1-indanylidene)acetamide

A solution of(E)-2-(3-((tert-butyldimethylsilyl)oxy)-6-fluoro-1-indanylidene)acetamide (1.80 g, 5.6 mmoles) and pyridinium p-toluenesulfonate (0.85g, 3.4 mmoles, Aldrich) in ethanol (65 mL) was heated at 55°-68° C. for3.5 hours under a nitrogen atmosphere and evaporated in vacuo. Theresidue was dissolved in ethyl acetate (150 mL) and washed successivelywith water (2×150 mL) and brine (150 mL), dried over magnesium sulfate,filtered and evaporated in vacuo. The residue was chromatographed onsilica gel eluting with ethyl acetate, gradually increasing the polarityto ethyl acetate: ethanol (95:5). The fractions containing the majorspot were combined and evaporated in vacuo, and the residue was dried ina vacuum at 80° C. for 18 hours to give 0.72 g (62%) of(E)-2-(6-fluoro-3-hydroxy-1-indanylidene)acetamide as a white solid, mp166°-168° C.;

EXAMPLE 24 Preparation of (Z)-2-(2.3-dihydroxy-6-fluoro-1-indanylidene)acetamide

a) Preparation of (Z)-2-(2,3-dibromo-6-fluoro-1-indanylidene)acetamide

N-Bromosuccinimide (49.37 g, 277.4 mmoles, Aldrich) and benzoyl peroxide(1.60 g, 6.6 mmoles, Aldrich) were added to a suspension of(E)-2-(6-fluoro-1-indanylidene)acetamide (17.68 g, 92.5 mmoles) incarbon tetrachloride (335 mL) and benzene (335 mL). The mixture wasrefluxed under a calcium chloride drying tube for four hours, afterwhich time an orange solution formed. The heat was removed, and thesolution was stirred at ambient temperature for 18 hours. The mixturewas filtered, and the solids were washed with ethyl acetate. Thewashings and filtrate were combined and evaporated in vacuo. The residuewas dissolved in ethyl acetate (800 mL) and washed with water (3×200 mL)and brine (200 mL), dried over sodium sulfate, filtered and evaporatedin vacuo. The residue was chromatographed on silica gel eluting withhexane: ethyl acetate (2:1). The fractions containing the compound withRf =0.4 in hexane : ethyl acetate (1:1) were combined andchromatographed again on silica gel eluting with hexane: ethyl acetate(2:1). The fractions containing the compound with Rf=0.4 in hexane:ethyl acetate (1:1) were combined and evaporated in vacuo to give asolid which was washed with hexane and dried in a vacuum at 50° C. for18 hours to give 1.35 g (4%) of(Z)-2-(2,3-dibromo-6-fluoro-1-indanylidene) acetamide as a yellow solid,mp 158°-163° C. (decomposed).

b) A mixture of(Z)-2-(2,3-dibromo-6-fluoro-1-indanylidene)acetamide(0.54 g, 1.55 mmoles) and silver carbonate (0.56 g, 2.03 mmoles,Aldrich) in dimethoxyethane (15 mL) and water (30 mL) was refluxed for 6hours. The mixture was stirred overnight at ambient temperature andrefluxed again for 6 hours. The mixture was diluted with water (100 mL)and extracted with ethyl acetate (6×30 mL). The combined extracts werewashed with water (100 mL) and brine (100 mL), and evaporated in vacuo.The residue was chromatographed on silica gel, eluting with hexane:ethyl acetate (2:1). The fractions containing the compound with Rf=0.15,eluting with ethyl acetate, were combined and evaporated in vacuo togive 0.12 g (35%) of crude (Z)-2-(2,3-dihydroxy-6-fluoro-1-indanylidene)acetamide as a beige solid. Recrystallization from ethyl acetate: hexanemixtures gave 0.037 g (11%) of(Z)-2-(2,3-dihydroxy-6-fluoro-1-indanylidene)acetamide as an off-whitesolid which was shown by ¹ H-NMR to be a mixture (85:15) ofdiastereomers, mp 212°-220° C.; ¹ H-NMR (DMSO-d₆): d 7.82 (d, 2H),7.28-7.76 (m, 3H), 6.96 (s, 1H), 6.80 (s, 0.15H), 6.54 (s, 0.85H), 6.51and 6.12 (m, 0.3H), 5.92 (d, 1H), 4.81 (m, 1.7H); steady-state nOe:irradiation at 6.47 d, observed 20% nOe at 7.38 d.

EXAMPLE 25 Preparation of (E)-2-(6-Fluoro-3-oxo-1-indanylidene)acetamide

a) Preparation of (E)-Ethyl 3-fluorocinnamate

This compound was prepared in an analogous manner to Example 18a withthe replacement of 4'-fluoroacetophenone with 3-fluorobenzaldehyde (33.6g, 0.3 mmol Aldrich). Distillation gave 32.85 g (56%) of (E)-ethyl3-fluorocinnamate in 5 fractions (b.p., 140°-155° C. at 15 Torr) whichwere equally contaminated with approximately 13% of triethylphosphonoacetate. This material was used without additionalpurification. ¹ H NMR (DMSO-d₆): d 7.66-7.47 (m, 2H), 7.45-7.40 (m, 1H),7.27-7.20 (m, 1H), 6.70 (d, 1H, J_(HH) =16 Hz), 4.18 (q, 2H, J_(HH) =7.2Hz), 4.10-3.96 (m, 0.78H), 3.77 (d, 0.26H, J_(PH) =21.3 Hz), 1.24 (t,3H, J_(HH) =7.0 Hz), 1.24-1.14 (m, 1.17H).

b) Preparation of Diethyl 2-carbethoxy-3-(3-fluorophenyl)glutarate

Sodium metal (0.388 g, 0.0169 mol) was stirred in diethyl malonate(15.28 g, 0.0953 mol, Aldrich) under a nitrogen atmosphere at 120° C for0.33 hr. To the resulting solution was added (E)-ethyl 3-fluorocinnamate(16.4 g, 0.0845 mol) and stirring was continued for 7 hrs at the sametemperature. The dark solution was cooled, dissolved in dichloromethane(500 ml) and made acidic with 30 ml of 1N aqueous hydrochloric acid(Macintosh). The volatiles were removed from the resulting froth by spinevaporation in vacuo and the residue was dissolved in ethyl acetate.This solution was washed with 5% aqueous sodium bicarbonate untilneutral, water, and the volatiles were removed by spin evaporation invacuo. Distillation gave 20 g of a material boiling between 130°-185° C.at 0.150 Torr. Redistillation gave 14.72 g (44%) of diethyl2-carbethoxy-3-(3-fluorophenyl)glutarate as a clear liquid: b.p.,155°-160° C. at 0.1 Torr;

c) Preparation of 3-(3-Fluorophenyl)glutaric acid

To a hot solution of sodium hydroxide (19.15 g, 0.479 mol) in water (50ml) was added a solution of diethyl2-carbethoxy-3-(3-fluorophenyl)glutarate (18.8 g, 0.0532 mol) in ethanol(36 ml). The resulting slurry was refluxed for 5 hrs. The mixture waspoured into icewater and the ethanol was removed by spin evaporation invacuo. The residual aqueous solution was acidified with concentratedhydrochloric acid (12N) and the solution (200 ml) was extracted withethyl acetate (3×300 ml). The ethyl acetate layers were combined, washedwith water (50 ml) and the volatiles were removed by spin evaporation invacuo to give a solid that was recrystallized from dichloromethane andhexanes to give 9.3 g (77%) of 3-(3-fluorophenyl)glutaric acid a whitesolid; m.p., 126°-127.5° C.;

d) Preparation of 2-(6-Fluoro-3-oxo-1-indanyl)acetic acid

Polyphosphoric acid (39.6 g, Aldrich) and 3-(3-fluorophenyl)glutaricacid (6.6 g, 0.0292 mol) were combined and the mixture heated with anoil bath at 120° C. for 10 min. The now red solution was cooled toapproximately 60° C. and water (approximately 100 ml) was addeddropwise, with efficient stirring. The resulting precipitate wascollected and washed with water. Recrystallization from dichloromethaneand hexanes gave 5.3 g (87%) of 2-(6-fluoro-3-oxo-1-indanyl)acetic acid:m.p., 150°-151° C.;

e) Preparation of 2-(6-Fluoro-3-oxo-1-indanyl)acetyl chloride

Oxalyl chloride (4.5 g, 0.035 mol, Aldrich) was added to an ice coldstirring mixture of 2-(6-fluoro-3-oxo-1-indanyl)acetic acid (5.0 g,0.024 mol) in dichloromethane (200 ml) under a nitrogen atmosphere. Themixture was allowed to warm to room temperature and stirring wascontinued for 48 hrs. The volatiles were removed from the solution byspin evaporation in vacuo with the addition of dichloromethane (3×50 ml)to give 2-(6-fluoro-3-oxo-1-indanyl)acetyl chloride which was usedwithout purification or analysis.

f) Preparation of 2-(6-Fluoro-3-oxo-1-indanyl)acetamide

A solution of 2-(6-fluoro-3-oxo-1-indanyl)acetyl chloride (prepared from0.024 mol of 2-(6-fluoro-3-oxo-1-indanyl)acetic acid) in dichloromethane(150 ml) was cooled to 0C and stirred rapidly while 50 ml of ammoniumhydroxide, 28-30%, was added. The resulting mixture was allowed to warmto room temperature and stirring was continued for 18 hr. The volatilesfrom this mixture were removed by spin evaporation in vacuo and theresidue was dissolved in dichloromethane (250 ml) and washed with water(3×50 ml). The dichloromethane phase was then slurried with Silica Gel60 and the volatiles were removed by spin evaporation in vacuo. Thissilica was then applied to a column of Silica Gel 60 (51×400 mm) wetwith dichloromethane and the product was removed by elution withmethanol:dichloromethane (3:97) to give, after recrystallization frommethanol, 2.4 g (48%) of 2-(6-fluoro-3-oxo-1-indanyl)acetamide as ayellow solid: m.p., 150°-152° C.;

g) Preparation of (E)2-(6-Fluoro-3-oxo-1-indanylidene)acetamide

A mixture of 2-(6-fluoro-3-oxo-1-indanyl)acetamide (0.750 g, 0.0036mol), N-bromosuccinimide (0.750 g, 0.0042 mol, Aldrich), benzoylperoxide (0.270 g, 0.0011 mol, Aldrich) in tetrachloromethane (37 ml)and benzene (37 ml) was stirred while heating with an oil bath at 120°C. for 20 min. This reaction was combined with a similarly run reaction(except 0.0024 mol scale). The solution was slurried with Silica Gel 60and the volatiles were removed by spin evaporation in vacuo. This silicagel was then applied to a column of Silica Gel 60 (51×450 mm) wet withdichloromethane and the product was removed by elution withmethanol:dichloromethane (3:97). After the volatiles were removed fromthe combined fractions containing product by spin evaporation in vacuo,the residue was recrystallized from methanol to give 0.81 g (58%) of(E)-2-(6-fluoro-3-oxo-1-indanylidene)acetamide: m.p., 235° C. (dec.):

EXAMPLE 26 Preparation of(E)-N-Cyclopropyl-2-(6-fluoro-3-ethyl-1-indanylidene)acetamide

a) Preparation of Ethyl 3-(4-fluorophenyl)pentenoate

A solution of butyllithium, 1.6M in hexanes (230 ml,0.368 mol, Aldrich)was added dropwise over 0.5 hr, with rapid mechanical stirring, to asolution of triethyl phosphonoacetate (78.9 g, 0.351 mol, Aldrich) intetrahydrofuran (800 ml, anhydrous, Aldrich) at <5° C. while blanketedwith a nitrogen atmosphere. This solution was stirred for an additional0.25 hr and cooled to -5° C. with a methanol:ice bath and a solution of4'-fluoropropiophenone (50 g,0.328 mol, Aldrich) in tetrahydrofiran (50ml) was then added in one portion. Stirring was continued for 18 hrwithout additional cooling. The solution was concentrated to a goldenyellow sludge by spin evaporation in vacuo and diluted to 1000 ml withethyl acetate. After washing with deionized water (3×100 ml) thissolution was concentrated by spin evaporation in vacuo. Distillation atreduced pressure gave 45.65 g (63%) of ethyl3-(4-fluorophenyl)pentenoate as a mixture of (E) and (Z) isomers (ratio1:1) contaminated with 30% of triethyl phosphonoacetate as a clearliquid, b.p. 140°-146° C. at aspirator pressure;

b) Preparation of Ethyl 3-(4-Fluorophenyl)valerate

A mixture of ethyl 3-(4-fluorophenyl)pentenoate (45.65 g,0.137 mol) and10% palladium on carbon (0.86 g, Aldrich) in 95 % ethanol was shakenunder 4 atm hydrogen pressure in a Parr hydrogenator for 1.5 hr. Themixture was filtered and concentrated by spin evaporation in vacuo.Fractional distillation gave 38.95 g (63%) of ethyl3-(4-fluorophenyl)valerate as a clear oil contaminated with 29% triethylphosphonoacetate. b.p., 133°-142° C. at 17 mm Hg;

c) Preparation of 3-(4-Flurophenyl)valeric acid

This compound was prepared in an analogous manner to Example 18c withthe replacement of 3-(4-fluorophenyl)butyrate with ethyl3-(4-fluorophenyl)valerate (38.95 g 0.144 mol, containing 29% triethylphosphoneacetate) and using an excess of 85% potassium hydroxide (18.05g, 0.273 mol, Mallinckrodt). The dichloromethane layers were combined,washed with deionized water (50 ml) and concentrated by spin evaporationin vacuo. The residue was crystallized from hexanes to give 23.47 g(83%) of 3-(4-flurophenyl)valeric acid as a white crystalline solid: NMR(DMSO-d₆): d 12 (s, 1H), 7.28-7.24 (m, 2H), 7.14-7.08 (m, 2H), 2.91-2.89(m, 1H), 2.64-2.41 (m, 2H), 1.66-162 (m, 1H), 1.56-1.51 (m, 1H), 0.71(t, 3H, J=7.3 Hz).

d) Preparation of 3-(4-Fluorophenyl)valeroyl chloride

This compound was prepared in an analogous manner to Example 18d withthe replacement of 3-(4-fluorophenyl)butyric acid with3-(4-fluorophenyl)valeric acid (23.47g, 0.120 mol). The volatiles wereremoved by spin evaporation in vacuo with the addition ofdichloromethane (6×250 ml) during concentration to give 25.25 g (98%) of3-(4-fluorphenyl)valeroyl chloride as a golden yellow liquid: NMR(DMSO-d₆): d 7.3-7.22 (m, 2H), 7.15-7.06 (m, 2H), 2.98-2.73 (m, 1H),2.66-2.38 (m, 2H), 1.74-1.37 (m,2H), 0.70 (t, 3H, J=7.2 Hz).

e) Preparation of 3-Ethyl-6-fluoro-1-indanone

This compound was prepared in an analogous manner to Example 18e withthe replacement of 3-(4-fluorophenyl)butyryl chloride with3-(4-fluorophenyl)valeroyl chloride(25.27 g, 0.118 mol). Thedichloromethane extractions were combined, washed with deionized water(100 ml) and concentrated by spin evaporation in vacuo The residue waschromatographed on Silica Gel 60 using a step gradient going fromhexanes to ethyl acetate:hexanes/1:1. Fractions containing3-ethyl-6-fluoro-1-indanone were combined and concentrated by spinevaporation in vacuo with dichloromethane (2×150 ml) added duringconcentration to give 17.48 g (83%) of 3-ethyl-6-fluoro-1-indanone as acanary yellow syrup: NMR (DMSO-d₆): d 7.74-7.7 (dd, 1H, J_(HF) =8.4 Hz,J_(HH) =4.8 Hz), 7.6-7.53 (ddd, 1H, J_(HF) =9.0 Hz, J_(HH) =9.0 Hz and2.7 Hz), 7.37 (dd, 1H,J_(HF) =7.8 Hz, J_(HH) =2.4 Hz), ˜3.3(m, 1H,partially obscured by water), 2.88 (dd,1H, J_(gem) =19.2 Hz, J=7.6 Hz),2.39 (dd, 1H, J_(gem) =19.2 Hz, J=2.4 Hz), 1.98-1.90 (m, 1H), 1.54-1.44(m, 1H), 0.90 (t, 3H, J=7.3 Hz).

f) Preparation of cis and trans Ethyl2-(3-ethyl-6-fluoro-1-hydroxy-1-indanyl)acetate

This compound was prepared in an analogous manner to Example 18f withreplacement of 6-fluoro-3-methyl-1-indanone with3-ethyl-6-fluoro-1-indanone (17.3 g, 0.097 mol). Removal of thevolatiles from the workup solution gave 25.17 g (97%) of cis and transethyl 2-(3-ethyl-6-fluoro-1 -hydroxy-1-indanyl)acetate as a goldenyellow oil: NMR (DMSO-d₆): d 7.23-7.21 (m,1H), 7.13-7.06 (m, 2H), 5.48(s, 1H), 4.0 (q, 2H, J=7.2 Hz), 2.90-2.82 (m, 1H), 2.80-2.73 (m, 1H),2.70-2.55 (m, 2H), 2.04-1.9 (m,1H), 1.83-167 (m, 1H), 1.46-1.28 (m, 1H),1.11 (t,3H, J=7.1 Hz), 0.95 (t, 3H, J=7.3 Hz).

g) Preparation of (E)-2-(3-Ethyl-6-fluoro-1-indanylidene)acetic acid

This compound was prepared in an analogous manner with Example 18g withthe replacement of ethyl2-(6-fluoro-1-hydroxy-3-methyl-1-indanyl)acetate with ethyl2-(3-ethyl-6-fluoro-1-hydroxy-1-indanyl)acetate (24.85 g, 0.093 mol).Removal of the volatiles from the workup gave a beige residue.Recrystallization from dichloromethane-hexanes gave 12.91 g (63%) of(E)-2-(3-ethyl-6-fluoro-1-indanylidene)acetic acid as a whitecrystalline solid, m.p., 145°-148° C.;

h) Preparation of (E)-2-(3-ethyl-6-fluoro-1-indanylidene)acetyl chloride

This compound was prepared in an analogous manner to Example 18h withreplacement of (E)-2-(6-fluoro-3-methyl- 1 -indanylidene)acetic acidwith (E)-2-(3-ethyl-6-fluoro-1-indanylidene)acetic acid (5.7 g. 25.88mmol). The product residue was dissolved in dichloromethane and usedwithout purification in Example 26.

i) Preparation of(E)-N-Cyclopropyl-2-(6-fluoro-3-ethyl-1-indanylidene)acetamide

This compound was prepared in an analogous manner to Example 20 with thereplacement of (E)-2-(6fluoro-3-methyl-1-indanylidene)acetyl chloridewith (E)-2-(3-ethyl-6-fluoro-1-indanylidene)acetyl chloride (3.18 g,13.3 mmol). Recrystallization from dichloromethane-hexanes gave 2.24 g(65%) of (E)-N-cyclopropyl-2-(6-fluoro-3-ethyl-1-indanylidene)acetamideas a white crystalline solid, m.p., 143°-147° C.;

EXAMPLE 27 Preparation of(E-N-Cyclopropyl-2-(6-fluoro-3-propyl-1-indanylidene)acetamide

a) Preparation of 4' fluorobutyrophenone

Aluminum chloride (139 g, 1.04 mol) was added to a solution of butyrylchloride (55.45 g, 0.520 mol, Aldrich) in dichloromethane (500 ml)stirring under a nitrogen atmosphere at 25° C. A solution offluorobenzene (50.1 g, 0.521 mol, Aldrich) in dichloromethane was addedand stirring was continued for 18 h. The reaction solution was pouredover ice and extracted with dichloromethane (3×400 ml) . The combineddichloromethane extractions were washed with deionized water (2×250 ml),1.0N hydrochloric acid (500 ml), saturated sodium bicarbonate solution(2×500 ml) and deionized water (4×250 ml),concentrated by spinevaporation in vacuo. This material was combined with material from asimilar preparation (using 0.26 mol of fluorobenzene) for distillation.Distillation at reduced pressure gave 69.27 g (53%) of4'-fluorobutyrophenone as a pale yellow liquid which later partiallycrystallized, b.p. 108°-112° C. at 30 millitorr: NMR (DMSO-d₆): d 8.03(q, 2H, J=9.0 Hz and 5.6 Hz), 7.31 (t, 2H, J=8.9 Hz), 2.97 (t, 2H, J=7.0Hz), 1.65-1.55 (m, 2H), 0.91 (t, 3H, J=7.3 Hz).

b) Preparation of Ethyl 3-(4-fluorophenyl)hexenoate

A solution of butyllithium, 2.5M in hexanes (166 ml, 0.416 mol, Aldrich)was added dropwise over 0.5 hr, with rapid mechanical stirring, to asolution of triethyl phosphonoacetate (93.2 g, 0.416 mol, Aldrich) intetrahydrofuran (700 ml, anhydrous,Aldrich) at <5° C. while blanketedwith a nitrogen atmosphere. This solution was stirred for an additional0.25 hr and cooled to -5° C. with a methanol:ice bath and a solution of4'-fluorobutyrophenone (69 g, 0.416 mol, Aldrich) in tetrahydrofuran(150 ml) was then added in one portion. Stirring was continued for 18 hrwithout additional cooling. The solution was concentrated to a darkcamel sludge by spin evaporation in vacuo and diluted to 600 ml withdeionized water. The aqueous solution was extracted with dichloromethane(5×500 ml) and the dichloromethane was concentrated by spin evaporationin vacuo. Distillation at reduced pressure gave 58.5 g (60%) of ethyl3-(4-fluorophenyl) hexenoate as a mixture of (E) and (Z) isomers (ratio1:1) as clear liquid, b.p. 140°-150° C. at aspirator pressure;

c) Preparation of Ethyl 3-(4-Fluorophenyl)hexanoate

A mixture of ethyl 3-(4-fluorophenyl)hexenoate (58.12 g, 0.246 mol) and10% palladium on carbon (1.1 g, Aldrich) in 95% ethanol was shaken in aParr hydrogenator under a pressure of 2-4 atm of hydrogen for 0.75 hr.The mixture was filtered and concentrated by spin evaporation in vacuoto give 58.4 g (99.6%) of ethyl 3-(4-fluorophenyl)hexanoate as a clearliquid, NMR (DMSO-d₆): d 7.27-7.20 (m, 2H), 7.12-7.04 (m, 2H), 3.91 (q,2H, J=7.2 Hz), 2.99 (m, 1H), 2.66-2.59 (m, 1H), 2.52-2.44 (m, 1H,partially obscured by DMSO), 1.59-1.46 (m, 2H), 1.13-1.07 (m, 2H), 1.02(t, 3H, J=7.2Hz), 0.78 (t, 3H, J=7.5 Hz).

d) Preparation of 3-(4-Fluorophenyl)hexanoic acid

This compound was prepared in an analogous manner to Example 65c withthe replacement of 3-(4-fluorophenyl)valerate with ethyl3-(4-fluorophenyl) hexanoate (58 g, 0.243 mol). The dichloromethanelayers were combined, washed with deionized water (250 ml) andconcentrated by spin evaporation in vacuo. The residue was coevaporatedwith hexanes (200 ml) to give 46.81 g (92%) of3-(4-fluorophenyl)hexanoic acid as a pale yellow oil;

e) Preparation of 3-(4-Fluorophenyl)hexanoyl chloride

This compound was prepared in an analogous manner to Example 18d withthe replacement of 3-(4-fluorophenyl)butyric acid with3-(4-fluorophenyl)hexanoic acid (46.5 g, 0.222 mol). The volatiles wereremoved by spin evaporation in vacuo with the addition ofdichloromethane (5×250 ml) during concentration to give 50.01 g (99%) of3-(4-fluorophenyl)hexanoyl chloride as a golden yellow liquid;

f) Preparation of 6-fluoro-3-propyl-1-indanone

This compound was prepared in an analogous manner to Example 18e withthe replacement of 3-(4-fluorophenyl)butyryl chloride with3-(4-fluorophenyl) hexanoyl chloride (49.95 g, 0.218 mol). Thedichloromethane extractions were combined, washed with deionized water(250 ml) and concentrated by spin evaporation in vacuo. The residue wascoevaporated with dichloromethane (100 ml) to give 41.26 g (98%) of6-fluoro-3-propyl-1-indanone as a golden yellow syrup;

g) Preparation of cis and trans Ethyl2-(6-fluoro-1-hydroxy-3-propyl-1-indanyl)acetate

This compound was prepared in an analogous manner to Example 18f withreplacement of 6-fluoro-3-methyl-1-indanone with6-fluoro-3-propyl-1-indanone (40.75 g, 0.212 mol). Removal of thevolatiles from the workup solution gave 57.48 g (97%) of cis and transethyl 2-(6-fluoro-1-hydroxy-3-propyl-1-indanyl)acetate as a goldenyellow oil;

h) Preparation of (E)-2-(6-Fluoro-3-propyl-1-indanylidene)acetic acid

This compound was prepared in an analogous manner with Example 18g withthe replacement of ethyl2-(6-fluoro-1-hydroxy-3-methyl-1-indanyl)acetate with ethyl2-(6-fluoro-1-hydroxy-3-propyl-1-indanyl)acetate (57.12 g, 0.204 mol).Removal of the volatiles from the workup gave a golden yellow residue.The residue was slurried in hexanes to give 24.49 g (51%) of(E)-2-(6-fluoro-3-propyl-1-indanylidene)acetic acid as a whitecrystalline solid, m.p., 141°-144° C.: NMR (DMSO-d₆);

i) Preparation of (E)-2-(6-Fluoro-3-propyl-1-indanylidene)acetylchloride

This compound was prepared in an analogous manner to Example 18h withreplacement of (E)-2-(6-fluoro-3-methyl-1-indanylidnene)acetic acid with(E)-2-(6-fluoro-3-propyl-1-indanylidene)acetic acid (15.01 g, 64.07mmol). The product residue was dissolved in dichloromethane and usedwithout purification in Example 27j.

j) Preparation of(E)-N-Cyclopropyl-2-(6-fluoro-3-propyl-1-indanylidene)acetamide

This compound was prepared in an analogous manner to Example 20 with thereplacement of (E)-2-(6-fluoro-3-methyl- I -indanylidene)acetyl chloridewith (E)-2-(6-fluoro-3-propyl-1-indanylidene)acetyl chloride (3.26 g,0.013 mol). The volatiles were removed by spin evaporation in vacuo togive a golden yellow oil. The oil was chromatographed on Silica Gel 60with a step gradient of hexanes to ethyl acetate-hexanes (1:1).Fractions containing(E)-N-cyclopropyl-2-(6fluoro-3-propyl-1-indanylidene)acetamide werecombined and concentrated by spin evaporation in vacuo with hexanes(4×250 ml) added during concentration to give 2.09 g (59%) of(E)-N-Cyclopropyl-2-(6-fluoro-3-propyl-1-indanylidene)acetamide as awhite powdery solid, m.p. 94°-97° C.;

EXAMPLE 28 Preparation of (Z)-2-(6-Fluoro-1-indanylidene)acetamide

A solution of (E)-2-(6-fluoro-1-indanylidene)acetamide (20 g,104.6 mmol)in dichloromethane:methanol(3:1) (1000 ml) was irradiated by anCanrad-Hanovia quartz, mercury-vapor photochemical immersion lamp, 450wattts (Ace Glass, 7825-35) for 0.5 h. The volatiles were removed byspin evaporation in vacuo to give a beige residue. This residue waschromatographed on Silica Gel 60 using a step gradient going from ethylacetate: hexanes(1:1) to ethyl acetate:ethanol(1:1). Fractionscontaining (Z)-2-(6-fluoro-1-indanylidene)acetamide were combined andconcentrated by spin evaporation in vacuo. The resulting solid wasslurried in hexanes to give 7.2 g (37%) of(Z)-2-(6-fluoro-1-indanylidene)acetamide as a white crystalline solid,m.p.,175°-177 ° C.;

EXAMPLE 29 Preparation of(E)-2-(4,6-Difluoro-3-oxo-1-indanylidene)acetamide

a) Preparation of2,4-Dicarbethoxy-3-(3,5-difluorophenyl)-5-hydroxy-5-methyl-1-cyclohexanone

Slightly warm, liquid 3,5-difluorobenzaldehyde (5.0 g, 0.0352 mol,Aldrich), 95% ethanol (1.75 ml), and piperidine (0.7 ml) were added,with stirring, to ethyl acetoacetate (9.2 g, 0.0704 mol, Aldrich). Thesolution was stirred until homogeneous and was then placed in a waterbath to control the slightly exothermic reaction. After 4 hrs, thecrystalline mass was dissolved in warm dichloromethane (100 ml).Dilution with hexanes (300 ml) gave a turbid solution. After standingfor 24 hrs, the crystalline product was collected by filtration andwashed with hexanes to give 8.0 g (59%) of2,4-dicarbethoxy-3-(3,5-difluorophenyl)-5-hydroxy-5-methyl-1-cyclohexanone:m.p., 185°-186° C.;

b) Preparation of 3-(3,5-Difluorophenyl)glutaric acid

To a hot (95° C.) solution prepared from sodium hydroxide (322 g, 8.1mol) and deionized water (322 ml) was added a mixture of2,4-diacetyl-3-(3,5-difluorophenyl)-5-hydroxy-5-methyl-1-cyclohexanone(43 g, 0. 112 mol) in ethanol (322 ml) with rapid stirring. Theresulting mixture was refluxed for 4 hrs using an oil bath at 140° C.The ethanol was removed by spin evaporation in vacuo and the resultingslurry was cooled with an ice bath, and concentrated hydrochloric acid(12N) was added to adjust the pH to approximately 1. The precipitate wasdissolved by the addition of water, and this aqueous solution wasextracted with ethyl acetate (total volume 1500 ml). The ethyl acetateextracts were combined, washed with water, dried with MgSO₄, and thevolatiles were removed by spin evaporation in vacuo. Recrystallizationof the residue from dichloromethane and hexanes gave 9.10 g (33%) of3-(3,5-difluorophenyl)glutaric acid: m.p., 170°-172° C.;

c) Preparation of 2-(4,6-Difluoro-3-oxo-1-indanyl)acetic acid

This compound was prepared in an analogous manner to that of Example 25dwith the replacement of 3-(3-fluorophenyl)glutaric acid with3-(3,5-difluorophenyl)glutaric acid (9.02 g, 36.9 mmol) and an increaseof the heating time from 10 min to 30 min. Chromatography of thecollected product on a column of Silica Gel 60 (51×450 mm) withmethanol: dichloromethane (4:96) gave a material which wasrecrystallized from water to give 1.93 g (23%) of2-(4,6-difluoro-3-oxo-1-indanyl)acetic acid: m.p., 170°-172° C.;

d) Preparation of 2-(4,6-difluoro-3-oxo-1-indanyl)acetyl chloride

This compound was prepared in an analogous manner to that of Example 25ewith the replacement of 2-(6-fluoro-3-oxo-1-indanyl)acetic acid with2-(4,6-difluoro-3-oxo-1-indanyl)acetic acid (3.85 g, 0.017 mol). The2-(4,6-difluoro-3-oxo-1-indanyl)acetyl chloride thus prepared was usedwithout additional purification or analysis.

e) Preparation of 2-(4,6-Difluoro-3-oxo-1-indanyl)acetamide

This compound was prepared in an analogous manner to that of Example 25fwith the replacement of 2-(3-fluoro-3-oxo-1-indanyl)acetyl chloride with2-(4,6-difluoro-3-oxo-1-indanyl)acetic acid (4.2 g, 17 mmol). Afterchromatography, recrystallization twice from dichloromethane:hexanesgave 2.8 g (77%) of 2-(4,6-Difluoro-3-oxo-1-indanyl)acetamide: m.p.,155°-157° C.;

f) Preparation of (E)-2-(4,6-Difluoro-3-oxo-1-indanylidene)acetamide

A mixture of 2-(4,6-difluoro-3-oxo-1-indanyl)acetamide (1.0 g, 0.0044mol), N-bromosuccinimide (0.950 g, 0.00533 mol),2,2'-azobis(2-methylpropionitrile) (0.350 g, 0.00213 mol, Kodak),tetrachloromethane (50 ml) and benzene (50 ml) was heated with an oilbath at 120° C. for 1 hr. The reaction solution was diluted withdichloromethane, slurried with Silica Gel 60, and the volatiles wereremoved by spin evaporation in vacuo. This silica was then applied to acolumn of Silica Gel 60 (51×450 mm) wet with dichloromethane and theproduct was removed by elution with methanol:dichloromethane (2:98). Thevolatiles were removed by spin evaporation in vacuo to give 0.613 g of aresidue. This residue was recrystallized from methanol to give 0.302 g(31%) of (E)-2-(4,6-difluoro-3-oxo-1-indanylidene)acetamide: m.p., 250°C. (dec.);

EXAMPLE 30 Preparation of(E)-N-Ethyl-2-(7-fluoro-1,2,3,4-tetrahydro-1-naphthylidene)acetamide

a) Preparation of 2-Chloro-N-ethylacetamide

Chloroacetyl chloride (45 g, 398 mmoles, Aldrich) was added dropwise toaqueous ethylamine (70%, 30.7 g, 0.48 mol) in 100 ml of deionised wateroriginally at -20° C. with stirring. The temperature of the reaction wasraised to 0° C. and stirring was continued until the reaction was nolonger exothermic. The resulting solution was acidified withconcentrated hydrochloric acid (7 ml) and extracted with dichloromethane(4×250 ml). The organic layer was washed with deionised H₂ O (150 ml)filtered through glass wool and concentrated by spin evaporation invacuo to give a pale yellow liquid residue. This residue wasconcentrated with hexanes (200 ml) and dichloromethane (600 ml) to give16.01 g (59%) of 2-chloro-N-ethylacetamide. The spectra of this compoundwas consistent with the proposed structure and the compound was usedwithout further analysis.

b) Preparation of Diethyl (N-ethylcarbamoyl)methyl)phosphonate

2-Chloro-N-ethylacetamide (15.5 g, 127.5 mmol) was added in portionswith stirring to triethyl phosphite (28 g, 0.17 moles, Aldrich) at 110°C. The solution was then heated to 155° C. for 30 minutes, cooled to125° C., and the volatiles were removed by distillation under aspiratorvacuum (15 mm Hg) at this temperature. Fractional distillation gave25.06 g (88%) of diethyl ((N-ethylcarbamoyl)methyl) phosphonate; b.p.,135°-147° C. at 0.50 mm Hg. This compound was used without furtheranalysis.

c) Preparation of(E)-N-Ethyl-2-(7-fluoro-1,2,3,4-tetrahydro-1-naphthylidene) acetamide

To a stirred suspension of NaH (80% dispersion in mineral oil, 0.91 g,0.030 mol, Aldrich) in dimethyl sulfoxide (150 ml) at room temperatureunder a nitrogen atmosphere was added a solution of diethyl((N-ethylcarbamoyl)methyl phosphonate (6.8 g, 0.030 mol) in dimethylsulfoxide (50 ml). The reaction was slightly exothermic. The reactionwas stirred for 0.75 h. A solution of 7-fluoro-1-tetralone (5.00 g,0.030 mol) in dimethyl sulfoxide (50 ml) was added and the reaction wasstirred for 1 h. The reaction was poured into ice-cold water (300 ml)and extracted with diethyl ether (3×ml). The combined ether phases werewashed with water (100 ml) and concentrated by spin evaporation in vacuoto give a golden yellow syrup. This residue was chromatographed onSilica Gel 60 using a step gradient going from ethyl acetate-hexanes/1:3to ethyl acetate-hexanes/1:1. Fractions containing(E)-N-Ethyl-2-(7-fluoro-1,2,3,4-tetrahydro-1-naphthylidene acetamidewere combined and spin evaporated in vacuo to give 3.74 g of a whitesolid. Recrystallization from dichloromethane-hexanes gave 3.28 g (46%)of (E)-N-ethyl-2-(7-fluoro-1,2,3,4-tetrahydro-1-naphthylidene) acetamideas a fluffy white solid; m.p., 87°-89° C.

Anal.Calcd. for C₁₄ H₁₆ FNO (mw 233.278): C,72.08; H, 6.91; N, 6.00Found: C,72.05; H, 6.91; N, 6.05

EXAMPLE 31 Preparation of(Z)-N-Ethyl-2-(7-fluoro-1,2,3,4-tetrahydro-1-naphthylidene)acetamide

Fractions from the chromatographic purification described in Example 30that contained(Z)-N-ethyl-2-(7-fluoro-1,2,3,4-tetrahydro-1-naphthylidene)acetamidewere combined and concentrated in vacuo to give 1.07 g (20%) of(Z)-N-ethyl-2-(7-fluoro-1,2,3,4-tetrahydro-1-naphthylidene)acetamide asa while solid; m.p., 117°-118° C.

Anal.Calcd. for C₁₄ H₁₆ FNO (mw 233.278): C,72.08; H, 6.91; N,6.00.Found: C,71.99; H, 6.89; N,6.01.

EXAMPLE 32 Preparation of(E)-2-(4,6-difluoro-3-hydroxy-1-idanylidene)acetamide

A suspension of (E)-2-(4,6-difluoro-3-oxo-1-indanylidene)acetamide(0.100 g, 0.45 mmol) and sodium borohydride (0.017 g, 0.45 mmol) in 95%ethanol was stirred at ambient temperature for 2 hours. The mixture wascooled in an ice bath and quenched with 0.1N hydrochloric acid (3 mL).The ethanol was evaporated in vacuo, and the residue was dissolved inethyl acetate (50 mL), washed successively with water (2×3 mL) and brine(30 mL), dried over sodium sulfate, filtered, and evaporated in vacuo.The resudue was washed successively with cold ethyl acetate, hexane, anddiethyl ether to give 0.046 g (45%) of(E)-2-(4,6difluoro-3-hydroxy-1-indanylidene)acetamide as a white solid;mp 232°-237° C. (dec.) ¹ H-NMR (DMSO-d₆): δ7.06-7.42 (m, 4H), 6.49 (s,1H), 5.52 (d, 1H), 5.30 (m,1H), 3.44 (m,1H), 3.03 (d, 1H).

    __________________________________________________________________________    The following compounds were prepared by methods similar to those of the    indicated Examples    Ex.No.        Compound                           M.p.(°C.)                                                Method (Ex.No.)    __________________________________________________________________________    33  (E)-2-(6-Fluoro-3-ethyl-1-indanylidene)-N-methylacetamide                                           141-143                                                26    34  (E)-2-(6-Fluoro-3-ethyl-1-indanylidene)acetamide                                           163-166                                                15    35  (E)-2-(6-Fluoro-3-ethyl-1-indanylidene)-N-isopropylacetamide                                           127-130                                                26    36  (E)-2-(6-Fluoro-3-ethyl-1-indanylidene)-N,N-dimethylacetamide                                           79-82                                                26    37  (E)-2-(6-Fluoro-3-propyl-1-indanylidene)-N-methylacetamide                                           105-107                                                26    38  (E)-2-(6-Fluoro-3-propyl-1-indanylidene-N,N-dimethylacetamide                                           95-97                                                26    39  (E)-2-(6-Fluoro-3-propyl-1-indanylidene)-N-isopropylacetamide                                           108-110                                                26    40  (E)-2-(6-Fluoro-3-propyl-1-indanylidene)acetamide                                           167-169                                                15    41  (E)-4-(2-(6-Fluoro-1-indanylidene)acetyl)morpholine                                           133-136                                                4    42  (E)-2-(6-Fluoro-1-indanylidene)-N-isopropylacetamide                                           143-145                                                4    43  (E)-2-(6-Fluoro-1-indanylidene)-N-methylacetamide                                           201-205                                                4    44  (E)-N-Cyclobutyl-2-(6-fluoro-1-indanylidene)acetamide                                           137-139                                                4    45  (E)-2-(6-Fluoro-1-indanylidene)-N-propylacetamide                                           82-84                                                4    46  (E)-2-(6-Fluoro-1-indanylidene)-N,N-dimethylacetamide                                           74-77                                                4    47  (E)-N-Cyclopropyl-2-(5,6-difluoro-1-indanylidene)acetamide                                           169-171                                                4    48  (E)-2-(5,6-Difluoro-1-indanylidene)-N-methylacetamide                                           209-211                                                4    49  (E)-2-(5,6-Difluoro-1-indanylidene)acetamide                                           165-167                                                1    50  (E)-2-(5,7-Difluoro-1-indanylidene)acetamide                                           161-162                                                1    51  (E)-N-Cyclopropyl-2-(5,7-difluoro-1-indanylidene)acetamide                                           145-147                                                4    52  (E)-2-(5,7-Difluoro-1-indanylidene)-N-methylacetamide                                           193-195                                                4    53  (E)-2-(4,6-Difluoro-1-indanylidene)-N-isopropylacetamide                                           167-170                                                4    54  (E)-2-(4,6-Difluoro-1-indanylidene)-N,N-dimethylacetamide                                           105-106                                                4    55  (E)-2-(4,6-Difluoro-1-indanylidene)-N-ethylacetamide                                           130-132                                                4    56  (E)-N-Ethyl-2-(4,6-difluoro-1-indanylidene)-N-methylacetamide                                           96-98                                                4    57  (E)-2-(4,7-Difluoro-1-indanylidene)acetamide                                           167-169                                                5    58  (E)-2-(4,5-Difluoro-1-indanylidene)acetamide                                           195-197                                                5    59  (E)-N-Cyclopropyl-2-(4,5-difluoro-1-indanylidene)acetamide                                           135-137                                                4    60  (E)-N-Cyclopropyl-2-(4,7-difluoro-1-indanylidene)acetamide                                           134-136                                                4    61  (E)-2-(4,6-Difluoro-1-indanylidene)-N-methylacetamide                                           181-183                                                4    62  (E)-2-(7-Fluoro-1,2,3,4-tetrahydro-1-naphthylidene)acetamide                                           148-150                                                12    63  (E)-2-(6-Fluoro-3,4-dihydro-2H-1-benzopyran-4-ylidene)acetamide                                           155-157                                                5    64  (E )-2-(6-Fluoro-3,4-dihydro-2H-1-benzopyran-4-ylidene)-N-methylacetam        ide                                182-185                                                4    65  (E)-2-(7-Fluoro-1,2,3,4-tetrahydro-1-naphthylidene)-N-methylacetamide                                           115-118                                                30    66  (E)-2-(7-Fluoro-1,2,3,4-tetrahydro-1-naphthylidene)-N-isopropylacetami        de                                 144-146                                                30    67  (E)-2-(7-Fluoro-1,2,3,4-tetrahydro-1-naphthylidene)-N-propylacetamide                                           71-74                                                30    68  (E)-N-Cyclobutyl-2-(7-fluoro-1,2,3,4-tetrahydro-1-naphthylidene)acetam        ide                                159-162                                                30    69  (E)-4-(2-(7-Fluoro-1,2,3,4-tetrahydro-1-naphthylidene)acetyl)morpholin        e                                  96-99                                                30    70  (E)-N-Ethyl-2-(7-fluoro-1,2,3,4-tetrahydro-1-naphthylidene)-N-methylac        etamide                            66-68                                                14    71  (Z)-2-(7-Fluoro-1,2,3,4-tetrahydro-1-naphthylidene)acetamide                                           198-201                                                31    72  (E)- N-Cyclopropyl-2-(6-fluoro-3,4-dihydro-2H-1-benzopyran-4-ylidene)a        cetamide                           146-148                                                4    __________________________________________________________________________

Pharmaceutical Compositions

In the following Examples 73 to 78 the "Active Ingredient" is a compoundof formula (I) or a pharmaceutically acceptable salt or solvate thereof.

EXAMPLE 73 Tablet Compositions

The following compositions A, B and C are prepared by wet granulation ofthe ingredients with a solution of povidone, followed by addition ofmagnesium stearate and compression.

    ______________________________________                       mg/tablet                                mg/tablet    ______________________________________    Composition A    (a) Active ingredient                       250      250    (b) Lactose B.P.   210      26    (c) Povidone B.P.  15       9    (d) Sodium Starch Glycollate                       20       12    (e) Magnesium Stearate                       5        3                       500      300    Composition B    (a) Active ingredient                       250      250    (b) Lactose        150      --    (c) Avicel PH 101  60       26    (d) Povidone B.P.  15       9    (e) Sodium Starch Glycollate                       20       12    (f) Magnesium Stearate                       5        3                       500      300    Composition C    Active ingredient           100    Lactose                     200    Starch                      50    Povidone                    5    Magnesium Stearate          4                                359    ______________________________________

The following compositions, D and E, are prepared by direct compressionof the admixed ingredients. The lactose in composition E is of thedirect compression type (Dairy Crest--"Zeparox").

    ______________________________________                       mg/tablet    ______________________________________    Composition D    Active ingredient  250    Pregelatinized Starch NF15                       150                       400    Composition E    Active ingredient  250    Lactose            150    Avicel             100                       500    ______________________________________    Composition F (Controlled Release Formulation)    The composition is prepared by wet granulation of    the ingredients (below) with a solution of povidone    followed by the addition of magnesium stearate and    compression.                              mg/tablet    ______________________________________    (a)     Active ingredient 500    (b)     Hydroxypropylmethylcellulose                              112            (Methocel K4M Premium)    (c)     Lactose B.P.      53    (d)     Povidone B.P.     28    (e)     Magnesium Stearate                              7                              700    ______________________________________

EXAMPLE 74 Capsule Compositions

Composition A

A capsule composition is prepared by admixing the ingredients ofComposition D in Example 73 above and filling into a two-part hardgelatin capsule. Composition B (infra) is prepared in a similar manner.

    ______________________________________                        mg/capsule    ______________________________________    Composition B    (a) Active ingredient                        250    (b) Lactose B.P.    143    (c) Sodium Starch Glycollate                        25    (d) Magnesium Stearate                        2                        420    Composition C    (a) Active ingredient                        250    (b) Macrogol 4000 B.P.                        350                        600    Composition D    Active ingredient   250    Lecithin            100    Arachis Oil         100                        450    ______________________________________

Capsules of composition D are prepared by dispersing the activeingredient in the lecithin and arachis oil and filling the dispersioninto soft, elastic gelatin capsules.

    ______________________________________    Composition E      mg/capsule    ______________________________________    (a) Active ingredient                       100    (b) Lactose        300    (c) Magnesium Stearate                       2    (d) Sodium Lauryl Sulfate                       2    (e) Sodium Starch Glycollate                       50    (f) Talc, USP      25                       479    ______________________________________

A capsule composition is prepared by micronizing the active ingredientusing a GEM-T Type 1047 Jet Mill and admixing with the remainingingredients of Composition E and filling into a two-part hard gelatincapsule.

Composition F (Controlled Release Capsule)

The following controlled release capsule composition is prepared byextruding ingredients a, b and c using an extruder, followed byspheronization of the extrudate and drying. The dried pellets are thencoated with release-controlling membrane (d) and filled into atwo-piece, hard gelatin capsule.

    ______________________________________                       mg/capsule    ______________________________________    (a) Active ingredient                       250    (b) Microcrystalline Cellulose                       125    (c) Lactose B.P.   125    (d) Ethyl Cellulose                       13                       513    ______________________________________

EXAMPLE 75

    ______________________________________    Injectable Composition    ______________________________________    Active ingredient      0.200 g    95% Ethanol and PEG 400, 1:1 ratio    Sterile water          q.s. to 10 mL    ______________________________________

The active ingredient is dissolved in 95% Ethanol and PEG 400 (1:1). Thebatch is then made up to volume with the water and filtered through asterile micropore filter into a sterile 10 mL amber glass vial (type 1)and sealed with sterile closures and overseals.

EXAMPLE 76

    ______________________________________    Syrup    ______________________________________    Active ingredient     0.25 g    Sorbitol Solution     1.50 g    Glycerol              2.00 g    Sodium Benzoate       0.005 g    Flavor, Peach 17.42.3169                          0.0125 mL    Purified Water        q.s. to 5.00 mL    ______________________________________

The active ingredient is dissolved in a mixture of the glycerol and mostof the purified water. An aqueous solution of the sodium benzoate isthen added to the solution, followed by addition of the sorbitolsolution and finally the flavor. The volume is made up with purifiedwater and mixed well.

EXAMPLE 77

    ______________________________________    Suppository              mg/suppository    ______________________________________    Active ingredient        250    Hard Fat, B.P. (Witepsol H15 - Dynamit NoBel)                             1770                             2020    ______________________________________

One-fifth of the Witepsol H15 is melted in a steam-jacketed pan at 45°C. maximum. The active ingredient is sifted through a 200 μM sieve andadded to the molten base with mixing, using a Silverson fitted with acutting head, until smooth dispersion is achieved. Maintaining themixture at 45° C., the remaining Witepsol H15 is added to the suspensionand stirred to ensure a homogenous mix. The entire suspension is passedthrough a 250 μM stainless steel screen and, with continuous stirring,is allowed to cool to 40° C. At a temperature of 38° C. to 40° C., 2.02g of the mixture is filled into suitable, 2 mL plastic molds. Thesuppositories are allowed to cool to room temperature.

EXAMPLE 78

    ______________________________________    Pessaries        mg/pessary    ______________________________________    Active ingredient                     250    Anhydrate Dextrose                     380    Potato Starch    363    Magnesium Stearate                     7                     1000    ______________________________________

The above ingredients are mixed directly and pessaries prepared bydirect compression of the resulting mixture.

EXAMPLE 79 Central Muscle Relaxant Activity

Central muscle relaxant activity of compounds of formula (I) wasdetermined using a Straub tail test based on that described by K. O.Ellis and J. F. Carpenter, Neuropharrnacol, 13, 211 (1974).

The Straub tail test result is reported as an ED₅₀ in mg/kg. The ED₅₀ isdefined as the dose of compound administered, which prevents Straub tailin 50% of mice. The compound is administered by oral gavage 60 min.prior to scoring.

The side effect potential of these compounds was determined using themouse rotorod test as described by G. D. Novak and J. M. Zwolshei,J.Pharmacological. Methods, 10, 175 (1983). Rotorod result is reportedas ED₅₀ in mg/kg. The ED₅₀ is the dose which causes 50% of the animalsto fail to maintain position on a cylinder rotating at 11 r.p.m.

Antagonism of morphine-induced Straub tail reflects central musclerelaxant efficacy while failure in the rotorod test reflects sedationand incoordination. Determination of the ratio of rotorod failure toantagonism of morphine-induced Straub tail is a means of assessing sideeffect liability of central muscle relaxants (G. D. Novak, Drug Dev.Res., 2, 383 (1982).

    ______________________________________             Straub Tail Rotorod    Compound of             p.o. ED.sub.50,                         p.o. ED.sub.50,    Example No.             mg/kg.      mg/kg.    Rotorod/Straub Tail    ______________________________________    1        51          88        1.7    5        54          79        1.5    ______________________________________

EXAMPLE 80 Anticonvulsant Activity

Anticonvulsant activity of compounds of formula (I) was determined usinga method described by Mehta et al., J.Med.Chem., 24, 465 (1981).

The anticonvulsant activity is reported as an ED₅₀ in mg/kg. The ED₅₀for protection against maximal electroshock-induced convulsions was thedose which prevented hind limb extension in 50% of the animals. The ED₅₀for protection against Metrazol-induced convulsions was the dose whichprevented convulsions in 50% of the animals.

    ______________________________________    Compound of     i.p. ED.sub.50, mg/kg (rat)    Example No      MES      MET    ______________________________________    13              25 i.p.  5.2 p.o.    ______________________________________     MES  maximal electroshock     MET  metrazol

EXAMPLE 81 Anxiolytic Activity

Anxiolytic activity of compounds of formula (I) was measured using themethod of Geller and Seifter, J.Psychopharmacolgia, 1, 482 (1960) asmodified by Pollard and Howard, Psychopharmacology, 62, 117 (1979).Clinically efficacious anxiolytics increase punished responding. Theanxiolytic activity of the compound is reported as the lowest dosenecessary to produce a significant increase in punished responding inrats(MED).

    ______________________________________    Compound of Example No.                      p.o. MED, mg/kg    ______________________________________    13                3.13 p.o.    ______________________________________     MED  Minimal Effective Dose

EXAMPLE 82 Antiinflammatory Activity

Compounds of formula (I) possess anti-inflammatory activity asdemonstrated using a modification of the standard carrageenan pleurisyassay as described by R. Vinegar, J. F., Traux, and J. L. Selph(Pro.Soc. Exp. Biol. Med 143:711-714, 1973). The rats used in theseexperiments were Lewis males, weighing 160-180 g, assigned to groupsconsisting of 5 animals. Test compounds were given to fasted rats byoral gavage 0.5 hr prior to intrapleural injection of 50 mg carrageenan.After 4 hr, the pleural exudate was collected and the edema volume andcell number were determined. ED₅₀ values were estimated by linearregression analysis, and represent the doses at which a given drugproduced 50% inhibition of carrageenan-induced cell accumulation andedema formation within the rat pleural cavity.

    ______________________________________    Compound of      p.o. ED.sub.50, mg/kg    Example No.      Cells   Edema    ______________________________________    1                21      20    5                16      12    ______________________________________

EXAMPLE 83 Established Adjuvant Arthritis

Compounds of formula (I) also exhibit chronic anti-inflammatory activityas evidenced by inhibition of established adjuvant-induced polyarthritisin the rat. The procedures for this test have been described in detailby R. Vinegar, J. F. Truax, J. L. Selph, A. Lea, and P. R. Johnston (J.Immunopharmacol. 1:497-520, 1979). The rats used in these studies werefemale Lewis rats whose starting weight was 190±10 g. Arthritic ratswere assigned to treatment groups consisting of six animals each. Fedrats were dosed by oral gavage starting on day 21 post adjuvantinjection; therapy was continued until day 28. The incidence andseverity of arthritic lesions were assessed using a modification of thescoring procedure described by H. L. F. Currey and M. Ziff (J. Exp. Med.121:185-203, 1968). Briefly, the bilateral joints were scored forerythema, edema, and ankylosis as outlined below:

    ______________________________________                   Arbitrary Joint Score (range)    Joint Evaluated                   Right     Left    ______________________________________    Wrist          0-4       0-4    Ankle          0-4       0-4    Tarsus         0-4       0-4    Metacarpals    0-4       0-4    Metatarsals    0-4       0-4    ______________________________________

The maximal possible score per rat was 40. Experimental results wereanalyzed by one-way ANOVA, followed by post hoc comparisons of treatmenteffects versus untreated arthritic control using the Newman-Keuls test.The percent inhibition of each drug-treated group was calculated fromthe mean relative to the arthritic control. Compound of Example No. 5significantly (p<0.01) lowered arthritic scores on days 22, 25, and 27in rats with established adjuvant arthritis dosed b.i.d. with 50 mg/kg.Spleen weight and plasma fibrinogen were measured postmortem on day 27and were also significantly reduced (p<0.01).

EXAMPLE 84 Mild Analgesia

Compounds of formula (I) possess mild analgesic activity as demonstratedusing a modification of the trypsin-induced rat hind limb hyperalgesiaassay as described by R. Vinegar, J. F. Truax, J. L. Selph and P. R.Johnston (J. Pharmacol. Meth., 23:51-61, 1990). The rats used in thesestudies were Lewis male, weighing 160-180 g. and assigned to groupsconsisting of 5-6 animals. Test compounds were given to fasted rats byoral gavage 0.5 hours prior to the subplantar injection of 250 mgtrypsin in one hind limb. One hour later the rats were evaluated forhyperalgesia using an F-shaped mechanical force clamp on the injectedhind limb metatarsal area. Latency (seconds) to the algesic response(vocalization or flight) was determined, with 4 seconds being themaximum latency allowed. ED₅₀ values were estimated by linear regressionanalysis and represent the dose at which a given drug extended thelatency response to produce 50% inhibition using the formula: (4sec.-Control Latency)-(4 sec.-Test Latency)/4 sec.-Control Latency×100.

    ______________________________________    Compound of Example No.                      p.o. ED.sub.50, mg/kg    ______________________________________    5                 4.0    ______________________________________

EXAMPLE 85 Strong Analgesia

Compounds of formula (I) possess strong analgesic activity asdemonstrated using the phalanges algesic assay a modification of thetrypsin-induced rat hind limb hyperalgesia assay as described by R.Vinegar, J. F. Truax, J. L. Selph and P. R. Johnston (J. Pharmacol.Meth. 23:51-61, 1990)!. The rats used in these studies were Lewis maleweighing 160-180 g and assigned to groups of 5-6 animals. The phalangesalgesic assay is an algesic test (no hyperalgesia) in which testcompounds were given to fasted rats by oral gavage. One hour later anF-shaped mechanical force clamp was applied to the phalanges of one hindlimb which initiated an algesic response(vocalization or flight).Latency (seconds) to the algesic response was determined with 3 secondsmaximum allowed time. ED₅₀ values were estimated by linear regressionanalysis and represent the dose at which a given compound extended thelatency response to produce 50% inhibition using the formula: (3sec.-Control Latency)-(3 sec.-Test Latency)/3 sec.-Control Latency×100.

    ______________________________________    Compound of Example No.                      p.o. ED.sub.50, mg/kg    ______________________________________    5                 22    ______________________________________

EXAMPLE 86 Toxicity Data

(i) Compound of Example 1

Single doses (15, 45, 100 or 250 mg/kg) were administered by oral gavageto groups of four non-fasted male CD-1 mice (Charles River). The maximumtolerated dose was greater than 250 mg/kg as there were no deaths withinthe seven days post dosing.

(ii) Compound of Example 5

Single doses (5, 15, 40, 100, 250, 500 or 1000 mg/kg) were administeredby oral gavage to groups of four non-fasted male CD-1 mice (CharlesRiver). The maximum tolerated dose was greater than 1000 mg/kg as therewere no deaths within the seven days post dosing.

We claim:
 1. Compounds of formula (I) ##STR16## wherein R¹, R², R³ andR⁴ are each selected from hydrogen and fluoro and at least one and notmore than two is fluoro;R⁵ is selected from hydrogen and C₁ -C₄ alkyl;R⁶ is selected from hydrogen, C₁ -C₄ alkyl and hydroxy; or R⁵ and R⁶together with the ring carbon form a carbonyl group; R⁷ is selected fromhydrogen and hydroxy; R⁸ and R⁹ are each selected from hydrogen, C₁ -C₄alkyl and cyclo(C₃ or C₄) alkyl or together with the nitrogen form amorpholino group; and X is selected from a bond, methylene and --O-- andis always a bond or --O-- when any of R⁵, R⁶ and R⁷ is other thanhydrogen and is always a bond when R⁵ and R⁶ together with the ringcarbon form a carbonyl group; and salts and solvates thereof.
 2. Acompound of formula (I) according to claim 1, or a pharmaceuticallyacceptable salt or solvate thereof, for use in the medical treatment ofa mammal including a human being.
 3. A pharmaceutical compositioncomprising a compound of formula (I) according to claim 1, or apharmaceutically acceptable salt or solvate thereof together with anacceptable carrier therefor.
 4. A method for the treatment ofa) acondition associated with abnormally raised skeletal muscle tone; b) acondition associated with a convulsive state; c) anxiety; d) pain; or e)an inflammatory conditionin a mammal, in need thereof, including a humanbeing, the method comprising administering thereto a therapeuticallyeffective amount of a compound of formula (I) according to claim 1 or apharmaceutically acceptable salt or solvate thereof.
 5. A process forpreparing compounds of formula (I) and salts and solvates thereof whichcomprises:reacting an amine of formula NR⁸ R⁹ or a suitable derivativethereof with a compound of formula (II) ##STR17## wherein Z is a leavinggroup and R¹ to R⁹ and X are as defined in claim
 1. 6. A compoundaccording to claim 1 which is selected from the group consisting of(E)-2-(4,6,-difluoro-1-indanylidene)acetamide and(E)-2-(6-fluoro-1-indanylidene)acetamide.
 7. A compound according toclaim 1 which is selected from the group consisting of(E)-2-(6-fluoro-3-hydroxy-1-indanylidene)acetamide,(Z)-2-(6-fluoro-2-hydroxy-1-indanylidene)acetamide,(E)-2-(4,6-difluoro-3-hydroxy-1-indanylidene)acetamide and(Z)-2-(4,6-difluoro-2-hydroxy-1-indanylidene)acetamide.
 8. Apharmaceutical composition comprising a compound of claim 6, or apharmaceutically acceptable salt or solvate thereof, together with anacceptable carrier therefor.
 9. A pharmaceutical composition comprisinga composition of claim 7, or a pharmaceutically acceptable salt orsolvate thereof, together with an acceptable carrier therefor.